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Parathyroid Hormone, Calcitonin, and Vitamin D
NASA Technical Reports Server (NTRS)
Analyses of secretion of parathyroid hormone during tests of stimulation and suppression of hormone-secretory activity using infusions of EDTA and calcium, respectively, have established that, in contrast to previous views, secretion of the hormone is not autonomous in many patients that have adenomatous hyperparathyroidism, but is responsive to changes in blood-calcium concentration. These findings have led to a new understanding of the pathophysiology of hormone production in hyperparathy-roidism. A related application of the diagnostic use of the radioimmunoassay is the preoperative localization of parathyroid tumors and the distinction between adenomas and chief-cell hyperplasia. Work involving catheterization and radioimmunoassay of blood samples obtained from the subclavin and innominate veins and the venae cavae, led to localization in a high percentage of patients. However, this procedure has been adopted recently to detect hormone concentration in the small veins directly draining the parathyroid glands.
Potts, J. T.
Vitamin D metabolites and bioactive parathyroid hormone levels during Spacelab 2
NASA Technical Reports Server (NTRS)
The effect of an 8-day space flight (Spacelab mission 2) on plasma levels of the vitamin D and parathyroid hormones is investigated experimentally in four crew members. The results are presented in tables and graphs and briefly characterized. Parathyroid hormone levels remained normal throughout the flight, whereas vitamin D hormone levels increased significantly on day 1 but returned to normal by day 7.
Morey-Holton, Emily R.; Schnoes, Heinrich K.; Deluca, Hector F.; Phelps, Mary E.; Klein, Robert F.
Background Vitamin D deficiency and parathyroid hormone (PTH) excess are common among older adults and may adversely impact cardiovascular health. We evaluated associations of 25-hydroxyvitamin D (25-OHD) and PTH concentrations, separately, and in combination, with incident cardiovascular events and mortality during 14 years of follow-up in the Cardiovascular Health Study. Methods and results We studied 2,312 participants who were free of cardiovascular disease at baseline. We measured 25-OHD and intact PTH from previously frozen serum using mass spectrometry and a two-site immunoassay. Outcomes were adjudicated cases of myocardial infarction, heart failure, cardiovascular death, and all cause mortality. There were 384 participants (17%) who had serum 25-OHD concentrations <15 ng/ml and 570 (25%) who had serum PTH concentrations ? 65 pg/ml. After adjustment, each 10-ng/ml lower 25-OHD concentration was associated with a 9% greater (95% CI 2% to 17% greater) relative hazard of mortality and a 25% greater (95% CI 8% to 44% greater) relative hazard of myocardial infarction. Serum 25-OHD concentrations <15 ng/ml, were associated with a 29% greater (95% CI 5% to 55% greater) risk of mortality. Serum PTH concentrations ? 65 pg/ml were associated with a 30% greater risk of heart failure (95% CI 6% to 61% greater), but not other outcomes. There was no evidence of an interaction between serum 25-OHD and PTH concentrations and cardiovascular events. Conclusions Among older adults, 25-OHD deficiency is associated with myocardial infarction and mortality; PTH excess is associated with heart failure. Vitamin D and PTH might influence cardiovascular risk through divergent pathways. PMID:21939825
Kestenbaum, Bryan; Katz, Ronit; de Boer, Ian; Hoofnagle, Andy; Sarnak, Mark J; Shlipak, Michael G.; Jenny, Nancy S.; Siscovick, David S.
Vitamin D status and parathyroid hormone in obese children before and after weight loss
Objective: The roles of vitamin D and parathyroid hormone (PTH) are discussed controversially in obesity, and studies of these hormones in obese children are limited. Therefore, we studied the relationships between PTH, 1,25-dihydroxy-vitamin D (1,25-OH Vit D), 25-hydroxy-vitamin D (25-OH Vit D), weight status, and insulin sensitivity before and after weight loss in obese children. Methods: Fasting serum PTH, 1,25-OH
Thomas Reinehr; Gideon de Sousa; Ute Alexy; M Kersting; Werner Andler
Optimal vitamin D status and serum parathyroid hormone concentrations in African American women13
Background: Optimal vitamin D status for the prevention of osteo- porosis has been inferred from examinations of the serum 25- hydroxyvitamin D (25(OH)D) concentration below which there is an increase in serum parathyroid hormone (PTH). Objective: The objectives of the study were to ascertain whether a threshold for serum 25(OH)D exists below which serum PTH in- creases and whether persons
John F Aloia; Sonia A Talwar; Simcha Pollack; Martin Feuerman; James K Yeh
Vitamin D and parathyroid hormone in insulin resistance of abdominal obesity: cause or effect?
The objective was to examine whether there were causal links between vitamin D status, parathyroid hormone, insulin resistance (IR)\\/insulin sensitivity (IS) and the metabolic syndrome (MS). A total of 72 Caucasian men and women, aged 55.7�7.57 years, with body mass index 33.4�4.02 kg\\/m2 and abdominal obesity, were assessed for IR\\/IS based on three commonly used indices before and after 12
M J Soares; W Chan She Ping-Delfos; J L Sherriff; D H Nezhad; N K Cummings; Y Zhao
Objectives: To determine the prevalence of premenstrual symptoms (PMS) due to primary dysmenorrhea among a sample of university female students, and to explore possible association with vitamin D and parathyroid (PTH) levels, as well as frequency of consumption of dairy products. Design: A cross-sectional study. Setting: One Jordanian university. Subjects: A total of 177 female students aged between 18 and 24 years who experienced primary dysmenorrhea participated in the study and completed a self administered questionnaire to collect information concerning demographics, menstruation- related information, associated specified premenstrual symptoms, and consumption of dairy products. Plasma 25-hydroxyvitamin vitamin D level and intact parathyroid hormone level were measured. Results: Of the 177 participants 91.5% had two or more symptoms among which fatigue, mood swings, anxiety, abdominal bloating, and depression were the most prevalent symptoms. There was no evident association between presence of symptoms and vitamin D status, PTH level or dairy products consumption. Headaches and social withdrawal were significantly lower in those women who consumed high amounts of dairy products. Conclusion: Premenstrual symptoms are very common in young women with primary dysmenorrhea. PMS has no relation to levels of vitamin D, parathyroid hormone or dairy products consumption. Headache and social withdrawal may be affected by dairy product consumption. PMID:23202842
Obeidat, Bayan A.; Alchalabi, Haifa A.; Abdul-Razzak, Khalid K.; Al-Farras, Mudhaffar I.
NASA Technical Reports Server (NTRS)
The role of parathyroid hormone, calcitonin, and vitamin D in the control of calcium and bone metabolism was studied. Particular emphasis was placed on the physiological adaptation to weightlessness and, as a potential model for this purpose, on the immobilization characteristic of space flight or prolonged bed rest. The biosynthesis, control of secretion, and metabolism of these hormonal agents is considered.
Potts, J. T., Jr.; Swenson, K. G.
Studies suggest that optimal vitamin D status is required for the maximal effect of antiresorptive agents. We investigated the relationship between vitamin D status, serum parathyroid hormone (PTH) concentrations, and change in bone mineral density (BMD) following iv zoledronate and denosumab. We carried out a retrospective analysis of 111 patients, mean age 70 (SD 13) years, 89 women and 22 men, prescribed zoledronate and 43 postmenopausal women treated with denosumab for osteoporosis. We measured BMD at the lumbar spine (LS) and total hip (TH), serum 25 (OH) vitamin D, PTH, and bone turnover markers (plasma CTX, P1NP) at 1 year. In patients on zoledronate, BMD increased at the LS and TH (mean LS change [SEM] = 2.6 % [0.5 %], mean TH change = 1.05 % [0.5 %], p < 0.05). A significant increase in BMD was seen at the LS only in the denosumab group (p = 0.001). Significant decreases in CTX and P1NP were observed at 12 months in both treatment groups. At baseline and at 12 months, 34 % and 23 % of the patients on zoledronate had a serum vitamin D of <50 nmol/L, respectively. The mean PTH concentration in patients with 25 (OH) vitamin D <50 nmol/L was 44 ng/L (SEM 16.6). Patients with PTH concentration <44 ng/L had significantly higher increases in TH BMD compared to those with PTH >44 ng/L (zoledronate 1.9 [0.83] vs. -0.43 [0.81], p = 0.04; denosumab 4.1 [0.054] vs. -1.7 [0.04], p = 0.004). Optimal vitamin D status and PTH concentrations improve the skeletal response to zoledronate and denosumab. PMID:24509506
Mosali, P; Bernard, L; Wajed, J; Mohamed, Z; Ewang, M; Moore, A; Fogelman, I; Hampson, G
Correlation of bone histology with parathyroid hormone, vitamin D3, and radiology in end-stage renal disease. We analyzed transiliac bone biopsy specimens from 30 end-stage renal failure patients, taken at the time of admission for CAPD training. Results were compared with values of iPTH, bone alkaline phosphatase, 1,25-dihydroxyvitamin D3, skeletal survey, quantitative computed tomography (QCT) and single photon absorptiometry (SPA) bone
Alastair J Hutchison; Rick W Whitehouse; Helen F Boulton; Judy E Adams; E Barbara Mawer; Tony J Freemont; Ram Gokal
Vitamin D (25(OH)D) increases the efficiency of intestinal calcium absorption. Low levels of serum calcium stimulate the secretion of parathyroid hormone (PTH), which maintains serum calcium levels at the expense of increased bone turnover, bone loss and increased risk of fractures. We studied the association between 25(OH)D and PTH levels, and their associations with bone mineral density (BMD), bone loss,
Denise G. von M�hlen; Gail A. Greendale; Cedric F. Garland; Lori Wan; Elizabeth Barrett-Connor
In vivo in the rat 1,25(OH)2D3 decreases and a low calcium increases PTH mRNA levels. We now report the effect of 3 and 8 wk of changes in dietary vitamin D and calcium on PTH mRNA levels. PTH mRNA levels were increased by 3 wk of calcium deficiency (five times), a vitamin D-deficient diet (two times), and combined deficiency (10 times), but not changed by high calcium. Vitamin D-deficient-diet rats' PTH mRNA did not decrease after a single large dose of 1,25(OH)2D3, but did decrease partially after repeated daily doses of 1,25(OH)2D3. Rats after a vitamin D-, calcium-deficient (-D-Ca) diet did not respond to changes in serum calcium at 1 h. Flow cytometry of isolated cells from parathyroid-thyroid tissue separated the smaller parathyroid from the larger thyroid cells and allowed an analysis of parathyroid cell number. In normal vitamin D/normal calcium (NDNCa) rats the parathyroid cells were 24.7 +/- 3.4% (n = 6) of the total cell number, whereas in -D-Ca rats they were 41.8 +/- 6.6% (n = 6) (P less than 0.05). That is, -D-Ca rats had 1.7 times the number of cells, whereas they had 10 times the amount of PTH mRNA, indicating the major contribution (6 times) of increased PTH gene expression per cell. Moreover, a calcium-deficient, more so than a vitamin D-deficient diet, amplifies the expression of the PTH gene, and vitamin D is necessary for an intact response of PTH mRNA to 1,25(OH)2D3 or calcium. Images PMID:2212016
Naveh-Many, T; Silver, J
There is a lack of large-scale studies on vitamin D status and its relationship to parathyroid hormone (PTH) and bone turnover markers in adults living in Shanghai. The objectives were to determine the prevalence of vitamin D insufficiency in Shanghai and to investigate the relationship of 25(OH)D with parathyroid function and bone turnover markers. This cross-sectional study involved 649 men and 1939 women aged 20�89 years who were randomly sampled in Shanghai. Serum concentrations of 25(OH)D, PTH, albumin, and bone turnover markers were measured. During the winter season, the prevalence of vitamin D insufficiency (<30 ng/mL) was 84% in males and 89% in females. The prevalence of vitamin D deficiency (<20 ng/mL) was 30% in males and 46% in females. With increasing serum 25(OH)D concentrations categorized as <10, 10�20, 20�30, and ?30 ng/mL, the mean PTH and bone turnover markers levels gradually decreasd in both sexes (p<0.001). There was an inverse relationship between the serum 25(OH)D and PTH concentrations in both genders, but no threshold of 25(OH)D at which PTH levels plateaued was observed. There were modest but significantly inverse relationships between the levels of 25(OH)D and bone turnover markers, but no plateau was observed for serum 25(OH)D levels up to 40 ng/mL. PMID:23144810
Ke, Yao-Hua; He, Jin-Wei; Fu, Wen-Zhen; Zhang, Chang-Qing; Zhang, Zhen-Lin
Previous studies have yielded conflicting findings on the relationship between low vitamin D (25-OH-D) and impaired glucose homeostasis. In this context, we hypothesized that combined assessment of 25-OH-D with its regulator parathyroid hormone (PTH) may be required for optimal evaluation of the impact of vitamin D status on glucose metabolism. Thus, we evaluated the prospective associations of 25-OH-D and PTH at 3 months postpartum with ?-cell function (Insulin Secretion-Sensitivity Index-2 [ISSI-2]), insulin sensitivity (Matsuda index), and glycemia at 12 months postpartum in 494 women undergoing serial metabolic characterization. Notably, 32% of those with prediabetes/diabetes mellitus at 12 months postpartum had both vitamin D deficiency and PTH in the highest tertile at 3 months postpartum. On multiple-adjusted linear regression analyses, vitamin D deficiency/insufficiency with PTH in the highest tertile at 3 months independently predicted poorer ?-cell function (P = 0.03) and insulin sensitivity (P = 0.01) and increased fasting (P = 0.03) and 2-h glucose (P = 0.002) at 12 months postpartum. In contrast, vitamin D deficiency/insufficiency with lower PTH did not predict these outcomes. In conclusion, only vitamin D deficiency/insufficiency with increased PTH is an independent predictor of ?-cell dysfunction, insulin resistance, and glycemia, highlighting the need for consideration of the PTH/25-OH-D axis when studying the impact of vitamin D status on glucose homeostasis. PMID:24875346
Kramer, Caroline K; Swaminathan, Balakumar; Hanley, Anthony J; Connelly, Philip W; Sermer, Mathew; Zinman, Bernard; Retnakaran, Ravi
Aluminum, parathyroid hormone, and osteomalacia
Aluminum exposure in man is unavoidable. The occurrence of dialysis dementia, vitamin D-resistant osteomalacia, and hypochromic microcytic anemia in dialysis patients underscores the potential for aluminum toxicity. Although exposure via dialysate and hyperalimentation leads to significant tissue aluminum accumulation, the ubiquitous occurrence of aluminum and the severe pathology associated with large aluminum burdens suggest that smaller exposures via the gastrointestinal tract and lungs could represent an important, though largely unrecognized, public health problem. It is clear that some aluminum absorption occurs with the ingestion of small amounts of aluminum in the diet and medicines, and even greater aluminum absorption is seen in individuals consuming large amounts of aluminum present in antacids. Aluminum absorption is enhanced in the presence of elevated circulating parathyroid hormone. In addition, elevated PTH leads to the preferential deposition of aluminum in brain and bone. Consequently, PTH is likely to be involved in the pathogenesis of toxicities in those organs. PTH excess also seems to lead to the deposition of aluminum in the parathyroid gland. The in vitro demonstration that aluminum inhibits parathyroid hormone release is consistent with the findings of a euparathyroid state in dialysis patients with aluminum related vitamin D-resistant osteomalacia. Nevertheless, it seems likely that hyperparathyroidism is at least initially involved in the pathogenesis of aluminum neurotoxicity and osteomalacia; the increases in tissue aluminum stores are followed by suppression of parathyroid hormone release, which is required for the evolution of osteomalacia. Impaired renal function is not a prerequisite for increased tissue aluminum burdens, nor for aluminum-related organ toxicity. Consequently, it is likely that these diseases will be observed in populations other than those with chronic renal disease.
Burnatowska-Hledin, M.A.; Kaiser, L.; Mayor, G.H.
Background: Thus far the search for osteoporosis candidate genes has focused less attention on the regulation of calcium homeostasis. Associations of vitamin D receptor (VDR) FokI, calcium-sensing receptor (CaSR) A986S and parathyroid hormone (PTH) BstBI polymorphisms with calcium homeostasis and peripheral bone density were investigated in adult Finns. Methods: The subgroup of the population-based FINRISK survey consists of 339 healthy
M. M. L. Laaksonen; T. A. Outila; M. U. M. K�rkk�inen; V. E. Kemi; H. J. Rita; M. Perola; L. M. Valsta; C. J. E. Lamberg-Allardt
Vitamin D deficiency is very prevalent in dialysis and peritoneal dialysis (PD) patients show lower levels of cholecalciferol (25(OH)D3) than hemodialysis patients. We conducted a systematic narrative review to assess the effects of vitamin D therapy on control of secondary hyperparathyroidism and clinical outcomes induced by vitamin D pleiotropic effects. Medline database was searched for cohort and intervention studies reporting data on vitamin D (all sterols including synthetic analogs) and peritoneal dialysis without language restriction. Two authors independently extracted data. Twenty-nine observational and eleven interventional studies were identified for inclusion (1,036 subjects). PTH levels decreased in twenty-nine studies, increased in one study and remained stable in ten studies. Thirty-three studies analyzed the oral route for vitamin D administration, ten the intraperitoneal, one the subcutaneous and one the intravenous. A significant decrease of peritonitis risk was observed in two studies. Proteinuria decreased in four studies and remained stable in one study. Peritoneal protein loss decreased in one study and was stable in two studies. Studies on the therapeutic effects of vitamin D in PD are limited and describe small population samples. Moreover, vitamin D compounds do not consistently reduce PTH levels. The administration of active vitamin D in PD may have interesting pleiotropic effects such as decreasing proteinuria and peritoneal protein loss. According to these effects, vitamin D could help to preserve residual renal function and ensure efficient peritoneal membrane dialysance. PMID:25012237
Russo, Roberto; Ruospo, Marinella; Cozzolino, Mario; De Nicola, Luca; Icardi, Andrea; Paoletti, Ernesto; Mazzaferro, Sandro
In several low latitude countries, vitamin D deficiency is emerging as a public health issue. Adequate vitamin D is essential for bone health in rapidly growing children. In the Thai population, little is known about serum 25-hydroxyvitamin D [25(OH)D] status of infants and children. Moreover, the association between 25(OH)D and the biological active form of 1,25-dihydroxyvitamin D [1,25(OH)]2D is not clear. The specific aims of this study were to characterize circulating serum 25(OH)D, 1,25(OH)2D and their determinants including parathyroid hormone (PTH), age, sex, height and body mass index (BMI) in 529 school-aged Thai children aged 6�14 y. Adjusted linear regression analysis was performed to examine the impact of age and BMI, and its interaction with sex, on serum 25(OH)D concentrations and 1,25(OH)2D concentrations. Serum 25(OH)D, 1,25(OH)2D and PTH concentrations (geometric mean � geometric SD) were 72.7�1.2 nmol/L, 199.1�1.3 pmol/L and 35.0�1.5 ng/L, respectively. Only 4% (21 of 529) participants had a serum 25(OH)D level below 50 nmol/L. There was statistically significant evidence for an interaction between sex and age with regard to 25(OH)D concentrations. Specifically, 25(OH)D concentrations were 19% higher in males. Moreover, females experienced a statistically significant 4% decline in serum 25(OH)D levels for each increasing year of age (P?=?0.001); no decline was seen in male participants with increasing age (P?=?0.93). When BMI, age, sex, height and serum 25(OH)D were individually regressed on 1,25(OH)2D, height and sex were associated with 1,25(OH)2D with females exhibiting statistically significantly higher serum 1,25(OH)2D levels compared with males (P<0.001). Serum 1,25(OH)2D among our sample of children exhibiting fairly sufficient vitamin D status were higher than previous reports suggesting an adaptive mechanism to maximize calcium absorption. PMID:25111832
Houghton, Lisa A.; Gray, Andrew R.; Harper, Michelle J.; Winichagoon, Pattanee; Pongcharoen, Tippawan; Gowachirapant, Sueppong; Gibson, Rosalind S.
Vitamin D status and parathyroid hormone in a urban population in Vietnam
Summary��In this cross-sectional study in Vietnam, the prevalence of vitamin D insufficiency was 46% in adult women and 20% in adult\\u000a men. There was a linear inverse relationship between serum 25(OH)D and PTH concentrations, but there was no threshold of 25(OH)D\\u000a at which PTH levels plateaued.\\u000a \\u000a \\u000a \\u000a \\u000a Introduction��Vitamin D insufficiency is adversely associated with health outcomes. Vitamin D status in Asian
L. T. Ho-Pham; N. D. Nguyen; T. Q. Lai; J. A. Eisman; T. V. Nguyen
Objectives: To explore the associations of serum vitamin D and parathyroid hormone (PTH) levels with serum lipid profiles and the risk of hyperlipidemia in a middle-aged and elderly population.Methods: A population-based cross-sectional study was conducted in the spring of 2012 among 1,203 Chinese participants, aged 52 to 101 years. 25-Hydroxyvitamin D [25(OH)D] was measured by chemiluminescence assay. (PTH) levels were measured with an electrochemiluminescence immunoassay (ECLIA) method.Results: A total of 1,203 participants, including 526 women (43.7%), were evaluated in 2012. The median concentrations of serum 25(OH)D and PTH for the entire group were 17.3 ng/mL and 38.3 pg/mL, respectively. Serum 25(OH)D and PTH levels were not independently associated with serum total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol levels in a multivariate adjusted linear regression analysis of 1,027 participants not receiving antihyperlipidemic treatment (P>.05). In logistic regression analyses, serum 25(OH)D and PTH levels were not associated with a risk of hyperlipidemia after adjustment for age, sex, heavy drinking, smoking, diabetes, obesity, family history of hyperlipidemia, body mass index (BMI), physical activity, glomerular filtration rate (GFR), fasting glucose, high-sensitivity C-reactive protein (hsCRP), calcium, and hemoglobin.Conclusions: Serum 25(OH)D and PTH levels are not independently associated with serum lipid levels or an increased risk of hyperlipidemia in a middle-aged and elderly Chinese population. PMID:24449665
Chen, Wei Ren; Sha, Yuan; Chen, Yun Dai; Shi, Yang; Yin, Da Wei; Wang, Hao
Fibroblast growth factor (FGF) 23 is an important regulator of phosphaturia. Its serum level was found to increase before that of parathyroid hormone (PTH) in early chronic kidney disease (CKD) in some but not all previous studies. As vitamin D insufficiency is associated with elevated PTH, we determined the effect of vitamin D status on FGF23 and PTH levels in relation to glomerular filtration rate (GFR) in people with CKD stage 3. Serum intact FGF23, PTH, and 25(OH)vitamin D3 were measured in 1664 patients who were prospectively recruited from primary care. Mean or median values for key variables were an age of 73 years, estimated GFR (eGFR) of 53?ml/min per 1.73?m(2), PTH 46?pg/ml, FGF23 42?pg/ml, and 25(OH)vitamin D3 53?nmol/l. FGF23 and PTH concentrations were elevated in similar proportions of people with lower eGFR in the whole cohort. However, when 752 people with vitamin D insufficiency or deficiency were excluded, FGF23 was elevated in a greater proportion than PTH at all levels of eGFR. Conversely, among people with vitamin D insufficiency, PTH was elevated in a greater proportion than FGF23 at all GFR levels of ?40?ml/min per 1.73?m(2). In this cohort, we were able to triangulate the relationship between 25(OH)vitamin D3, PTH, and FGF23, showing that vitamin D status critically determines whether FGF23 or PTH becomes elevated first in the context of lower GFR. Future studies of FGF23 in people with CKD should routinely determine their vitamin D status. PMID:24429404
Taal, Maarten W; Thurston, Victoria; McIntyre, Natasha J; Fluck, Richard J; McIntyre, Christopher W
The British National Diet and Nutrition Survey of people aged 65 years and over in 1994-5 provided nationally representative estimates of food and nutrient intakes and biochemical status indices. In a further analysis study, parathyroid hormone (PTH) concentrations were measured in plasma samples from 773 subjects and were analyzed with the existing data on vitamin D intake, plasma 25-hydroxyvitamin D
C. J. Bates; G. D. Carter; G. D. Mishra; D. O'Shea; J. Jones; A. Prentice
Objective Vitamin D deficiency is prevalent in critically ill patients and may contribute to suboptimal clinical outcomes, but little is known about alterations of the calcium-parathyroid hormone (PTH)-vitamin D axis and prognosis in these individuals. Methods A prospective observational study was conducted on 216 patients admitted to a university-affiliated, tertiary-care medical intensive care unit(MICU) between June 2011 and December 2012. Serum levels of 25-hydroxyvitamin D, ionised calcium and intact PTH were determined within 24 h of MICU admission. The primary end point was all-cause hospital mortality within 90-days of admission. Results 95 patients (44%) showed 25-hydroxyvitamin D deficiency. Patients deficient in vitamin D showed significantly higher Acute Physiology and Chronic Health Evaluation II (APACHE II) score, rate of positive blood culture, incidence of multiple organ dysfunction syndrome, and 90-day mortality rate than did patients with vitamin D insufficiency or sufficiency (P<0.05), as well as lower levels of serum IgG. 25-Hydroxyvitamin D deficiency was identified as an independent risk factor for mortality (OR?=?3.018, 95%CI 1.329�6.854, P?=?0.008). Hypovitaminosis D in PTH-responders was associated with higher mortality than was the same condition in non-responders (P<0.05). Conclusions These results suggest that vitamin D deficiency is prevalent among MICU patients, suggesting a significant derangement of the calcium-PTH-vitamin D axis in critically ill patients. Vitamin D deficiency is an independent risk factor for 90-day mortality, and hypovitaminosis D in PTH-responders is associated with higher mortality than is the same condition in non-responders. PMID:24073266
Zhao, Xiaoqin; Chen, Qiang; Chen, Zhaoyan; Qin, Hua; Qin, Yingfen; Liang, Xinghuan; Suo, Yingjun
Calcium and vitamin D are essential nutrients for bone health. Periods of activity with repetitive mechanical loading, such as military training, may result in increases in parathyroid hormone (PTH), a key regulator of Ca metabolism, and may be linked to the development of stress fractures. Previous studies indicate that consumption of a Ca and vitamin D supplement may reduce stress fracture risk in female military personnel during initial military training, but circulating markers of Ca and bone metabolism and measures of bone density and strength have not been determined. This randomized, double-blind, placebo-controlled trial sought to determine the effects of providing supplemental Ca and vitamin D (Ca+Vit D, 2000mg and 1000IU/d, respectively), delivered as 2 snack bars per day throughout 9weeks of Army initial military training (or basic combat training, BCT) on PTH, vitamin D status, and measures of bone density and strength in personnel undergoing BCT, as well as independent effects of BCT on bone parameters. A total of 156 men and 87 women enrolled in Army BCT (Fort Sill, OK; 34.7�N latitude) volunteered for this study. Anthropometric, biochemical, and dietary intake data were collected pre- and post-BCT. In addition, peripheral quantitative computed tomography was utilized to assess tibia bone density and strength in a subset of volunteers (n=46). Consumption of supplemental Ca+Vit D increased circulating ionized Ca (group-by-time, P=0.022), maintained PTH (group-by-time, P=0.032), and increased the osteoprotegerin:RANKL ratio (group-by-time, P=0.006). Consistent with the biochemical markers, Ca+Vit D improved vBMD (group-by-time, P=0.024) at the 4% site and cortical BMC (group-by-time, P=0.028) and thickness (group-by-time, P=0.013) at the 14% site compared to placebo. These data demonstrate the benefit of supplemental Ca and vitamin D for maintaining bone health during periods of elevated bone turnover, such as initial military training. This trial was registered with ClincialTrials.gov, NCT01617109. PMID:25118085
Gaffney-Stomberg, Erin; Lutz, Laura J; Rood, Jennifer C; Cable, Sonya J; Pasiakos, Stefan M; Young, Andrew J; McClung, James P
In addition to the well-documented hyporesponsiveness of the kidney, resistance to parathyroid hormone (PTH) has been postulated for bone in pseudohypoparathyroidism type I (PHP). In some of these patients reduced bone density and even frank osteitis fibrosa suggest osteoclastic overactivity. To address the possibility that the skeletal system of patients with PHP may be affected by their increased PTH secretion
K. Kruse; U. Kracht; K. Wohlfart; U. Kruse
Determinants of Plasma Parathyroid Hormone Levels in Young Women
While the effects of calcium, phosphorus intake, and vitamin D on parathyroid hormone (PTH) have been well studied, less is\\u000a known about other factors that impact PTH. Our goal was to delineate associations between demographic, dietary, and plasma\\u000a factors and PTH. We conducted a cross-sectional study of intact PTH among 1,288 nonblack women in the Nurses Health Study\\u000a II aged
Julie M. PaikGary; Gary C. Curhan; John P. Forman; Eric N. Taylor
Background: The effects of vitamin D supplementation in healthy prepubertal children on physiologic outcomes have not been investigated. Objective: The objective was to evaluate the effects of supplementation with 1000 IU vitamin D3/d on calcium absorption. Design: In a double-blind, placebo-controlled trial, we randomly assigned 64 children to 1000 IU vitamin D3/d (n = 32) or placebo (n = 32) for 8 wk. Stable isotopes were used to assess calcium absorption. The main outcome measure was calcium absorption before and after supplementation. Results: All of the data are shown as means � SDs. At baseline, vitamin D intake was 221 � 79 IU/d and calcium intake was 830 � 197 mg/d. Baseline serum 25-hydroxyvitamin D [25(OH)D] was not significantly correlated with fractional or total calcium absorption. After 8 wk, with baseline values used as a covariate, no differences were seen in fractional or total calcium absorption based on supplementation group (P = 0.75 and 0.36, respectively). Supplemented children had a significant increase in 25(OH)D concentrations (from 27.7 � 7.4 to 36.0 � 10.3 ng/mL; P < 0.0001) and a decrease in parathyroid hormone (from 21.4 � 10.4 to 12.9 � 7.1 pg/mL; P < 0.001); no significant changes in the placebo group were observed. No adverse side effects were noted in either group. Conclusions: Vitamin D3 supplementation at 1000 IU/d increases 25(OH)D and decreases parathyroid hormone in children with average vitamin D intakes below the dietary recommendations of the Institute of Medicine. However, no significant effects of this change on calcium absorption occurred. This trial was registered at clinicaltrials.gov as NCT 00868738. PMID:23151536
Abrams, Steven A; Hawthorne, Keli M; Chen, Zhensheng
Introduction Combination antiretroviral therapy (cART) may affect vitamin D [25(OH)D], parathyroid hormone (PTH), bone mineral density (BMD) and bone turnover (BT). Reduced BMD and secondary hyperparathyroidism have been reported with tenofovir (TDF). We investigated the associations between TDF and bone markers, especially in 25(OH)D-deficient patients. Materials and Methods In a single-centre longitudinal study investigating BMD in HIV-positive men, serum 25(OH)D, calcium, phosphate, PTH and alkaline phosphatase (ALP) were measured. Lumbar spine, non-dominant total hip and non-dominant femoral neck BMD (g/cm2) were measured using dual-energy X-ray absorptiometry. BT was assessed by serum type 1 procollagen (P1NP) and carboxy-terminal collagen cross-links (CTX). Mann�Whitney U tests compared serum markers and BT, and t-tests compared BMD according to TDF in all and 25(OH)D-deficient patients. Results A total of 422 men were recruited: mean age 47 (SD 9.8) years, 94% white ethnicity, 93% MSM, diagnosed HIV positive for median 9.6 (IQR 5.0,15.5) years, median CD4 547 (IQR 411,696) cells/�L, HIV RNA <40 copies/mL in 87% (96% of those on cART). 25(OH)D (nmol/L) was normal (>75), insufficient (50�75), deficient (25�50) and severely deficient (<25) in 14%, 29%, 50% and 7%, respectively. Of 381 men on cART, 77% were currently on TDF. TDF was not associated with median calcium (p=0.69) or phosphate (p=0.52), but patients had higher (but normal) median ALP [81 (IQR 69,103) vs. 73 (IQR 60,89) IU/L, p=0.005) compared to non-TDF cART. There was no difference in the association between vitamin D and PTH according to whether someone currently was (r=0.11, p=0.06, Figure 1) or was not using TDF (r=0.12, p=0.29, Figure 1). TDF was also not associated with PTH, BMD or BT in either all patients on cART (Table 1a) or in patients with 25(OH)D deficiency (Table 1b). Conclusions In this largely TDF-experienced cohort of HIV-positive men, there was no association between TDF and 25(OH)D deficiency, hyperparathyroidism, reduced BMD or increased BT, although patients on TDF had higher but normal ALP. We found no evidence to support additional monitoring of bone markers in patients on TDF regardless of 25(OH)D status.
Samarawickrama, Amanda; Jose, Sophie; Sabin, Caroline; Walker-Bone, Karen; Fisher, Martin; Gilleece, Yvonne
Background The interest on magnesium (Mg) has grown since clinical studies have shown the efficacy of Mg-containing phosphate binders. However, some concern has arisen for the potential effect of increased serum Mg on parathyroid hormone (PTH) secretion. Our objective was to evaluate the direct effect of Mg in the regulation of the parathyroid function; specifically, PTH secretion and the expression of parathyroid cell receptors: CaR, the vitamin D receptor (VDR) and FGFR1/Klotho. Methods The work was performed in vitro by incubating intact rat parathyroid glands in different calcium (Ca) and Mg concentrations. Results Increasing Mg concentrations from 0.5 to 2 mM produced a left shift of PTH�Ca curves. With Mg 5 mM, the secretory response was practically abolished. Mg was able to reduce PTH only if parathyroid glands were exposed to moderately low Ca concentrations; with normal�high Ca concentrations, the effect of Mg on PTH inhibition was minor or absent. After 6-h incubation at a Ca concentration of 1.0 mM, the expression of parathyroid CaR, VDR, FGFR1 and Klotho (at mRNA and protein levels) was increased with a Mg concentration of 2.0 when compared with 0.5 mM. Conclusions Mg reduces PTH secretion mainly when a moderate low calcium concentration is present; Mg also modulates parathyroid glands function through upregulation of the key cellular receptors CaR, VDR and FGF23/Klotho system. PMID:24103811
Rodriguez-Ortiz, Maria E.; Canalejo, Antonio; Herencia, Carmen; Martinez-Moreno, Julio M.; Peralta-Ramirez, Alan; Perez-Martinez, Pablo; Navarro-Gonzalez, Juan F.; Rodriguez, Mariano; Peter, Mirjam; Gundlach, Kristina; Steppan, Sonja; Passlick-Deetjen, Jutta; Munoz-Castaneda, Juan R.; Almaden, Yolanda
A G Protein-Linked Receptor for Parathyroid Hormone and Parathyroid Hormone-Related Peptide
The complementary DNA encoding a 585-amino acid parathyroid hormone-parathyroid hormone-related peptide (PTH-PTHrP) receptor with seven potential membrane-spanning domains was cloned by COS-7 expression using an opossum kidney cell complementary DNA (cDNA) library. The expressed receptor binds PTH and PTHrP with equal affinity, and both ligands equivalently stimulate adenylate cyclase. Striking homology with the calcitonin receptor and lack of homology with
Harald Juppner; Abdul-Badi Abou-Samra; Mason Freeman; Xiang F. Kong; Ernestina Schipani; Jennifer Richards; Lee F. Kolakowski Jr.; Janet Hock; John T. Potts Jr.; Henry M. Kronenberg; Gino V. Segre
Determination of Hormone Parathyroid by Radioimmunoassay.
National Technical Information Service (NTIS)
The labelling of bovine parathyroid hormone and its employment for the determination of seric PTH by radioimmunoanalysis is described. The specific activity of exp 131 I PTH is 200-350mCi/mg and the damage 3-5%. The method used for radioimmunoanalysis was...
C. Fisher-Ferraro, M. Moos de Ephraim, C. Mautalen, A. E. A. Mitta
Skeletal responsiveness to parathyroid hormone in pseudohypoparathyroidism
Background: Although there have been some case reports suggesting that bone in patients with pseudohypoparathyroidism (PHP) might respond to parathyroid hormone (PTH), no information is available as to whether serum PTH concentration is related to bone metabolic markers or to bone mineral density (BMD) in PHP. Objective: To address these relationships, by comparing intact serum PTH, bone metabolic markers and
Masanori Kanatani; Toshitsugu Sugimoto; Hiroshi Kaji; Kazuto Ikeda; Kazuo Chihara
21 CFR 862.1545 - Parathyroid hormone test system.
Code of Federal Regulations, 2011 CFR
...ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems � 862.1545 Parathyroid hormone test system. (a)...
21 CFR 862.1545 - Parathyroid hormone test system.
Code of Federal Regulations, 2013 CFR
...ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems � 862.1545 Parathyroid hormone test system. (a)...
21 CFR 862.1545 - Parathyroid hormone test system.
Code of Federal Regulations, 2010 CFR
...ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems � 862.1545 Parathyroid hormone test system. (a)...
The effects of dopaminergic agonists and antagonists have been studied in dispersed bovine parathyroid cells. Dopaminergic agonists caused a transient 20- to 40-fold increase in cellular cyclic AMP and a 2- to 3-fold increase in parathyroid hormone release. Dose-response relationships were similar for cyclic AMP accumulation and hormone release, whether studied by increasing agonist concentration or by increasing concentration of
E. M. Brown; R. J. Carroll; G. D. Aurbach
Steroid regulation of parathyroid hormone-related protein expression and action in the rat uterus
The gene encoding parathyroid hormone-related protein (PTHrP), an autocrine\\/paracrine inhibitor of vascular and nonvascular smooth muscle contractility, is regulated by hormonal steroids including estrogens (E2), 1,25-dihydroxy vitamin D (Vit D3) and glucocorticoids. While E2 increases PTHrP gene expression, Vit D3 and glucocorticoids inhibit transcriptional activity of this gene. In the uterus of ovariectomized rats, E2-treatment increases both PTHrP mRNA levels
V. Paspaliaris; D. N. Petersen; M. A. Thiede
Therapy of Hypoparathyroidism by Replacement with Parathyroid Hormone
Hypoparathyroidism (HypoPT) is a state of hypocalcemia due to inappropriate low levels of parathyroid hormone (PTH). HypoPT is normally treated by calcium supplements and activated vitamin D analogues. Although plasma calcium is normalized in response to conventional therapy, quality of life (QoL) seems impaired and patients are at increased risk of renal complications. A number of studies have suggested subcutaneous injections with PTH as an alternative therapy. By replacement with the missing hormone, urinary calcium may be lowered and QoL may improve. PTH replacement therapy (PTH-RT) possesses, nevertheless, a number of challenges. If PTH is injected only once a day, fluctuations in calcium levels may occur resulting in hypercalcemia in the hours following an injection. Twice-a-day injections seem to cause less fluctuation in plasma calcium but do stimulate bone turnover to above normal. Most recently, continuous delivery of PTH by pump has appeared as a feasible alternative to injections. Plasma calcium levels do not fluctuate, urinary calcium is lowered, and bone turnover is only stimulated modestly (into the normal range). Further studies are needed to assess the long-term effects. If beneficial, it seems likely that standard treatment of HypoPT in the future will change into replacement therapy with the missing hormone. PMID:25101193
Negative regulation of parathyroid hormone-related protein expression by steroid hormones
Highlights: {yields} Steroid hormones repress expression of PTHrP in the cell lines where the corresponding nuclear receptors are expressed. {yields} Nuclear receptors are required for suppression of PTHrP expression by steroid hormones, except for androgen receptor. {yields} Androgen-induced suppression of PTHrP expression appears to be mediated by estrogen receptor. -- Abstract: Elevated parathyroid hormone-related protein (PTHrP) is responsible for humoral hypercalcemia of malignancy (HHM), which is of clinical significance in treatment of terminal patients with malignancies. Steroid hormones were known to cause suppression of PTHrP expression. However, detailed studies linking multiple steroid hormones to PTHrP expression are lacking. Here we studied PTHrP expression in response to steroid hormones in four cell lines with excessive PTHrP production. Our study established that steroid hormones negatively regulate PTHrP expression. Vitamin D receptor, estrogen receptor {alpha}, glucocorticoid receptor, and progesterone receptor, were required for repression of PTHrP expression by the cognate ligands. A notable exception was the androgen receptor, which was dispensable for suppression of PTHrP expression in androgen-treated cells. We propose a pathway(s) involving nuclear receptors to suppress PTHrP expression.
Kajitani, Takashi; Tamamori-Adachi, Mimi [Department of Biochemistry, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605 (Japan)] [Department of Biochemistry, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605 (Japan); Okinaga, Hiroko [Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605 (Japan)] [Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605 (Japan); Chikamori, Minoru; Iizuka, Masayoshi [Department of Biochemistry, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605 (Japan)] [Department of Biochemistry, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605 (Japan); Okazaki, Tomoki, E-mail: firstname.lastname@example.com [Department of Biochemistry, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605 (Japan)] [Department of Biochemistry, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605 (Japan)
Cervical ultrasound combined with parathyroid hormone assay prior to parathyroid exploration
The purpose of this study was to analyse ultrasound (US) findings and US-guided fine needle aspirations (FNAs) for parathyroid hormone (PTH) in pre-operative evaluation prior to parathyroid exploration. Thirteen patients with primary hyperparathyroidism (pHTP) underwent cervical US combined with FNAs. Fourteen suspected lesions were aspirated and the patients were operated on. The US examinations were performed with a real-time scanner
Hanna M�k�r�inen; Takalo Raija; Kairaluoma Matti; Salmela Pasi
Parathyroid-hormone-related protein in sarcoidosis.
Parathyroid-hormone-related protein (PTHrP) is the main mediator of the humoral hypercalcemia of malignancy. It is also detected in many normal adult and fetal tissues. Altered calcium metabolism occurs in sarcoidosis, and two cases of sarcoidosis with hypercalcemia and elevated plasma PTHrP are described. An archival study of 20 lymph node biopsies with the pathological diagnosis of sarcoidosis was performed. Immunohistochemistry using a polyclonal antiserum to human PTHrP and in situ hybridization using a riboprobe to human PTHrP were performed on the lymph node biopsies. Immunohistochemistry for PTHrP was also performed on the biopsies from the two cases with elevated plasma levels. Immunohistochemical analysis detected PTHrP in macrophages within granulomata in 17 of the 20 (85%) biopsies. In situ hybridization detected a positive signal for messenger RNA in the granulomata of 11 of 19 (58%) biopsies. PTHrP immunoreactivity and PTHrP gene expression are present in sarcoid granulomata. PTHrP may contribute to the hypercalcemia of sarcoidosis. Images Figure 1 PMID:9422518
Zeimer, H. J.; Greenaway, T. M.; Slavin, J.; Hards, D. K.; Zhou, H.; Doery, J. C.; Hunter, A. N.; Duffield, A.; Martin, T. J.; Grill, V.
Circulating parathyroid hormone and calcitonin in rats after spaceflight
NASA Technical Reports Server (NTRS)
Parathyroid hormone and calcithonin, two major calcium-regulating hormones, were measured in the plasma of five experimental groups of rats to evaluate postflight calcium homeostasis after the 14-day Cosmos 2044 flight. Parathyroid hormone values were slightly higher in the flight animals (F) than in the appropriate cage and diet controls (S) (44 +/- 21 vs 21 +/- 4 pg/ml, P less than 0.05), but they were the same as in the vivarium controls (V), which had different housing and feeding schedules. The difference in F and V (22 +/- 11 vs 49 +/- 16 pg/ml, P less than 0.05) was most likely due to failure of circulating calcitonin in F to show the normal age-dependent increase which was demonstrated in age-matched controls in a separate experiment. Basal values for parathyroid hormone and calcitonin were unchanged after 2 wk of hindlimb suspension, a flight simulation model, in age-matched and younger rats. From a time course experiment serum calcium was higher and parathyroid hormone lower after 4 wk than in ambulatory controls. Postflight circulating levels of parathyroid hormone appear to reflect disturbances in calcium homeostasis from impaired renal function of undetermined cause, whereas levels of calcitonin reflect depression of a normal growth process.
Arnaud, Sara B.; Fung, Paul; Popova, Irina A.; Morey-Holton, Emily R.; Grindeland, Richard E.
Determinants of plasma parathyroid hormone levels in young women.
While the effects of calcium, phosphorus intake, and vitamin D on parathyroid hormone (PTH) have been well studied, less is known about other factors that impact PTH. Our goal was to delineate associations between demographic, dietary, and plasma factors and PTH. We conducted a cross-sectional study of intact PTH among 1,288 nonblack women in the Nurses Health Study II aged 33-53 with BMI <30 kg/m2 and eGFR > or = 60 ml/min/1.73 m2. Median PTH was 30.7 pg/ml. After adjusting for 25-hydroxyvitamin D and other factors, PTH was 4.1 pg/ml lower (95% CI -7.7 to -0.5) in women who smoked 1-14 cigarettes/day and 6.4 pg/ml lower (95% CI -11.2 to -1.7) in women who smoked >15 cigarettes/day compared to nonsmokers. After multivariate adjustment, women whose BMI was 27-29 kg/m2 had PTH levels 2.0 pg/ml higher (95% CI 0.2-3.9) compared to BMI of 21-22 kg/m2 and women in the highest quartile of plasma phosphorus had PTH levels 4.1 pg/ml lower (95% CI -5.8 to -2.4) than women in the lowest quartile. Higher vitamin A intake was independently associated with lower PTH, whereas lower calcium intake, lower plasma calcium, lower plasma 25-hydroxyvitamin D, and winter blood draw were associated with higher PTH. Intakes of phosphorus, animal protein, magnesium, alcohol, and caffeine were not associated with PTH. Factors not classically associated with calcium-phosphorus metabolism impact PTH. Additional research is needed to elucidate the mechanisms whereby smoking, vitamin A, and phosphorus affect PTH and to examine how body size and season may affect PTH independent of 25(OH)D. PMID:20631996
Paik, Julie M; Curhan, Gary C; Forman, John P; Taylor, Eric N
BACKGROUND: The prevalence of vitamin D insufficiency and secondary hyperparathyroidism is high among morbidly obese subjects. Further, low serum levels of 25-hydroxyvitamin D (25 [OH]D) and magnesium have been associated with increased risk of the metabolic syndrome (MS), and recently, a possible link between PTH and MS has been reported. Although it is well known that the synthesis and secretion
J�ran Hjelmes�th; Dag Hofs�; Erlend T Aasheim; Trond Jenssen; Johan Moan; Helle Hager; Jo R�islien; Jens Bollerslev
Parathyroid hormone concentration gradients across the human bone marrow
Summary��Parathyroid hormone (PTH) concentrations were compared in blood drawn from the bone marrow and antecubital vein of patients\\u000a undergoing marrow biopsy for suspected hematological neoplasia. Radioimmunological analysis revealed that the bone marrow\\u000a blood had a higher PTH content than blood from the peripheral circulation. Thyroid hormone-binding globulin was not distributed\\u000a asymmetrically, showing that the gradient is PTH specific. The intact
Michael John Atkinson; Heinrich Bodenstein; Rolf-Dieter Hesch
A Homologous Biological Probe for Parathyroid Hormone in Human Serum
A method of measuring the biological activity of parathyroid hormone (PTH) in human serum that depends on the activation of its natural target enzyme, human renal cortical adenylate cyclase, is described. Optimal sensitivity ranging in different assays from 14 to 20 pg 1�34 hPTH\\/ml was achieved in the presence of the GTP-analogue GppNHp (10 ?mol\\/L), 5 mmol\\/L MgCl2 and 1.25
Bettina Niepel; Heinfried Radeke; Michael J. Atkinson; Harald Jueppner; Rolf-Dieter Hesch
A cancer modifier role for parathyroid hormone-related protein
The parathyroid hormone-related protein (PTHrP) gene (Pthlh) maps in the distal region of mouse chromosome 6 that contains a quantitative trait locus associated with genetic predisposition to skin tumorigenesis. Here, we report a genetic polymorphism located in the osteostatin encoding region of the Pthlh gene and that produces Thr\\/Pro PTHrP variants. PthlhThr and PthlhPro alleles were significantly linked with resistance
Giacomo Manenti; Bernard Peissel; Manuela Gariboldi; F Stefania Falvella; Daniela Zaffaroni; Biagino Allaria; Simonetta Pazzaglia; Simonetta Rebessi; Vincenzo Covelli; Anna Saran; Tommaso A Dragani
Parathyroid Hormone Mediates Hematopoietic Cell Expansion through Interleukin6
Parathyroid hormone (PTH) stimulates hematopoietic cells through mechanisms of action that remain elusive. Interleukin-6 (IL-6) is upregulated by PTH and stimulates hematopoiesis. The purpose of this investigation was to identify actions of PTH and IL-6 in hematopoietic cell expansion. Bone marrow cultures from C57B6 mice were treated with fms-like tyrosine kinase-3 ligand (Flt-3L), PTH, Flt-3L plus PTH, or vehicle control.
Flavia Q. Pirih; Megan N. Michalski; Sun W. Cho; Amy J. Koh; Janice E. Berry; Eduardo Ghaname; Pachiyappan Kamarajan; Edith Bonnelye; Charles W. Ross; Yvonne L. Kapila; Pierre Jurdic; Laurie K. McCauley; Derya Unutmaz
Role of anions in parathyroid hormone release from dispersed bovine parathyroid cells.
It is known that permeant anions are required for the release of epinephrine from isolated chromaffin granules and of serotonin from intact platelets. We have now investigated the role of anions in the release of a polypeptide hormone, parathyroid hormone, from dispersed bovine parathyroid cells. The release is inhibited 60%-80% by decreasing either [Cl-] or [OH-] and 60%-70% by replacement of NaCl with the impermeant anion isethionate. By contrast, substitution of various monovalent cations in the medium had no effect on the release. Disodium 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonate (SITS) and probenecid, which are known to block anion transport in the erythrocyte, also cause a dose-dependent 90%-100% inhibition of release. Moreover, kinetic analysis of inhibition by probenecid suggests that it is competitive with respect to either OH- or Cl-. These results suggest that anions and the anion transport system may play a role in exocytosis of a polypeptide hormone. The proton ionophore carbonyl cyanide p-trifluoromethoxyphenylhydrazone was was also found to block hormone release, and the possibility is discussed of a "chemosmotic" mechanism for exocytosis in this system similar to that previously postulated for chromaffin granules and platelets. Images PMID:24845
Brown, E M; Pazoles, C J; Creutz, C E; Aurbach, G D; Pollard, H B
Parathyroid hormone-related protein (PTHrP) plays a vital role in the embryonic development of the skeleton and other tissues. When it is produced in excess by cancers it can cause hypercalcemia, and its local production by breast cancer cells has been implicated in the pathogenesis of bone metastasis formation in that disease. Antibodies have been developed that neutralize the action of PTHrP through its receptor, parathyroid hormone receptor 1, without influencing parathyroid hormone action through the same receptor. Such neutralizing antibodies against PTHrP are therapeutically effective in animal models of the humoral hypercalcemia of malignancy and of bone metastasis formation. We have determined the crystal structure of the complex between PTHrP (residues 1-108) and a neutralizing monoclonal anti-PTHrP antibody that reveals the only point of contact is an {alpha}-helical structure extending from residues 14-29. Another striking feature is that the same residues that interact with the antibody also interact with parathyroid hormone receptor 1, showing that the antibody and the receptor binding site on the hormone closely overlap. The structure explains how the antibody discriminates between the two hormones and provides information that could be used in the development of novel agonists and antagonists of their common receptor.
McKinstry, William J.; Polekhina, Galina; Diefenbach-Jagger, Hannelore; Ho, Patricia W.M.; Sato, Koh; Onuma, Etsuro; Gillespie, Matthew T.; Martin, T. John; Parker, Michael W.; (SVIMR-A); (Chugai); (Melbourne)
��Background: The success of parathyroid surgery depends on the identification and removal of all hyperactive parathyroid tissue.\\u000a At this writing, bilateral cervical exploration and identification of all parathyroid glands represent the operative standard\\u000a for primary hyperparathyroidism (pHPT). However, improved preoperative localization techniques and the availability of intraoperative\\u000a parathyroid hormone monitoring prepare the way for minimally invasive procedures. Methods: Patients with
K. K. J. Hallfeldt; A. Trupka; J. Gallwas; S. Schmidbauer
BACKGROUND: Parathyroid hormone increases bone strength primarily by stimulating bone formation, whereas antiresorptive drugs reduce bone resorption. We conducted a randomized, double-blind clinical study of parathyroid hormone and alendronate to test the hypothesis that the concurrent administration of the two agents would increase bone density more than the use of either one alone. METHODS: A total of 238 postmenopausal women
Dennis M. Black; Susan L. Greenspan; Kristine E. Ensrud; Lisa Palermo; Joan A. McGowan; Thomas F. Lang; Patrick Garnero; Mary L. Bouxsein; John P. Bilezikian; Clifford J. Rosen
Age-related increases in parathyroid hormone may be antecedent to both osteoporosis and dementia
BACKGROUND: Numerous studies have reported that age-induced increased parathyroid hormone plasma levels are associated with cognitive decline and dementia. Little is known about the correlation that may exist between neurological processing speed, cognition and bone density in cases of hyperparathyroidism. Thus, we decided to determine if parathyroid hormone levels correlate to processing speed and\\/or bone density. METHODS: The recruited subjects
Eric R Braverman; Thomas JH Chen; Amanda LC Chen; Vanessa Arcuri; Mallory M Kerner; Anish Bajaj; Javier Carbajal; Dasha Braverman; B William Downs; Kenneth Blum
Cloning and functional expression of a cDNA from the human cerebellum revealed a parathyroid hormone\\/parathyroid hormone-related peptide (PTH\\/PTHrP) receptor protein of 593 amino acids, identical in sequence to the PTH\\/PTHrP receptor of the human kidney and an osteoblast-like cell line (Schipani et al., Endocrinology, 132 (1993) 2157�2165). Expression of mRNA hybridizing with the cloned cDNA, indistinguishable in size on Northern
M. Eggenberger; B. Fl�hmann; R. Muff; M. Lauber; W. Lichtensteiger; W. Hunziker; J. A. Fischer; W. Born
Heterogeneity of Parathyroid Hormone. CLINICAL AND PHYSIOLOGIC IMPLICATIONS
When immunoreactive human parathyroid hormone (hPTH), extracted by three different solvents (20% acetone in 1% acetic acid, 8 M urea, or normal saline) from parathyroid glandular tissue was subjected to Sephadex G-100 gel filtration and immunoassay using two different antisera (273 and C-329), four distinct fractions were observed. The first (I), a void volume peak, was detected by both antisera with similar immunoreactivity, as was a second (II), which had the elution and sedimentation properties of highly purified bovine parathyroid hormone (bPTH); a third (III) eluted between [125I]growth hormone and [125I]insulin, sedimented with the velocity of a molecule of approximately 6,000 mol wt, and was detected primarily by antiserum 273; a final fraction (IV), detected primarily by C-329, eluted just prior to [125I]insulin. The elution profiles of the acetone-acetic acid and 8 M urea extracts were similar and contained fraction II as their major component. In saline extracts, however, fraction III predominated. Three fractions, having gel filtration and immunologic characteristics similar to fractions II, III, and IV, respectively, of saline glandular extracts, were detected in the plasma of patients with both primary (adenomatous or carcinomatous) and secondary hyperparathyroidism. The predominant component in every plasma was the intermediate fraction that, like III, was detected primarily by antiserum 273, while the least abundant form was consistently the final fraction, detected primarily by antiserum C-329. The first fraction, like II, was detected with about equal potency by both antisera and had an elution volume on Sephadex corresponding to that of intact bPTH. It bore a reciprocal relationship to serum calcium and disappeared from the plasma of a uremic patient during calcium infusion or following parathyroidectomy with a half-time of no more than 20 min. This component therefore probably represents biologically active hormone. The intermediate and final fractions had turnover times in the plasma of a uremic patient more than 100 times greater than the active form, remained elevated even in the presence of post-parathyroidectomy hypoparathyroidism in this patient and were presumed to be biologically inactive. The ratio of biologically inactive fragments to the active form was greater in secondary hyperparathyroidism. The evidence presented favors a glandular origin for the fragments. Comparison of hormonal assays with the two antisera reveals a striking advantage in the preoperative diagnosis of primary hyperparathyroidism with antiserum 273 that is due to the enhanced sensitivity occasioned by its detection of a biologically inactive as well as the biologically active hormonal form. Images PMID:4719672
Silverman, Robert; Yalow, Rosalyn S.
Osteoblast hydraulic conductivity is regulated by calcitonin and parathyroid hormone
NASA Technical Reports Server (NTRS)
It is our hypothesis that osteoblasts play a major role in regulating bone (re)modeling by regulating interstitial fluid (ISF) flow through individual bone compartments. We hypothesize that osteoblasts of the blood-bone membrane lining the bone surfaces are capable of regulating transosseous fluid flow. This regulatory function of the osteoblasts was tested in vitro by culturing a layer of rat calvarial osteoblasts on porous membranes. Such a layer of osteoblasts subjected to 7.3 mm Hg of hydrostatic pressure posed a significant resistance to fluid flow across the cell layer similar in magnitude to the resistance posed by endothelial monolayers in vitro. The hydraulic conductivity, the volumetric fluid flux per unit pressure drop, of the osteoblast layer was altered in response to certain hormones. Hydraulic conductivity decreased approximately 40% in response to 33 nM parathyroid hormone, while it exhibited biphasic behavior in response to calcitonin: increased 40% in response to 100 nM calcitonin and decreased 40% in response to 1000 nM calcitonin. Further, activation of adenylate cyclase by forskolin dramatically increased the hydraulic conductivity, while elevation of intracellular calcium, [Ca2+]i, by the calcium ionophore A23187 initially decreased the hydraulic conductivity at 5 minutes before increasing conductivity by 30 minutes. These results suggest that cyclic adenosine monophosphate (cAMP) and [Ca2+]i may mediate changes in the osteoblast hydraulic conductivity. The increase in hydraulic conductivity in response to 100 nM calcitonin and the decrease in response to PTH suggest that the stimulatory and inhibitory effects on bone formation of calcitonin and parathyroid hormone, respectively, may be due in part to alterations in bone fluid flow.
Hillsley, M. V.; Frangos, J. A.
Objective: A significant decrease in vitamin D receptor (VDR) and calcium-sensing receptor (CaSR) protein expression has been demonstrated recently in parathyroid (PT) adenomas. In this study, we investigated the relationships between the proliferative activity of parathyroid glands (PTGs) and the expression of VDR as well as CaSR, and compared it with the clinical severity in patients with primary hyperparathyroidism (18HPT).
Shozo Yano; Toshitsugu Sugimoto; Tatsuo Tsukamoto; Kazuo Chihara; Akira Kobayashi; Sohei Kitazawa; Sakan Maeda; Riko Kitazawa
Summary��An in vitro perifusion system was used to study parathyroid hormone (PTH) secretion in response to calcium (Ca) and beta-adrenergic\\u000a agents. Perifused parathyroid tissue responded to changes in Ca within the physiologic range during experiments up to 5 h.\\u000a There was rapid secretory stimulation after exposure to low Ca, with the maximum response being observed at 20 min. Normal\\u000a bovine
David A. Hanley; Kensuke Takatsuki; Maria E. Birnbaumer; Arthur B. Schneider; Louis M. Sherwood
The effect of continuous infusion of human parathyroid hormone on bone architecture in female mice
This research sought to create an animal model of secondary hyperparathyroidism through continuous infusion of parathyroid hormone (PTH) in adult female mice, and to subsequently study the catabolic effects of PTH. Osmotic ...
Eisenberg, Rahel E. (Rahel Esther)
Excessive production of parathyroid hormone-related protein (PTHrP) by tumor-like synoviocytes contributes to joint destruction in rheumatoid arthritis (RA). Having previously demonstrated that curcuminoid-only and essential ...
Frye, J.; Timmermann, Barbara N.; Funk, J.
Background��Secondary hyperparathyroidism (SHPTH) is present in many patients with end-stage renal disease (ESRD) and has been linked\\u000a to uremic bone disease. Parathyroid hormone (PTH) levels are affected by calcium, vitamin D, and phosphorus. Recent data suggests\\u000a that serum magnesium may also modulate PTH levels.\\u000a \\u000a \\u000a \\u000a Objective��The aim of this retrospective study was to investigate the impact of different calcium (Ca) and
Mingxin Wei; Khaled Esbaei; Joanne M. Bargman; Dimitrios G. Oreopoulos
Four antisera raised against partly purified PTH preparations all showed a wide range of specificities when reacting with radioiodinated PTH peptides representing several different portions of the intact hormone sequence. In contrast, antisera raised against individual peptides were only able to cross-react with other peptides that contained all or part of their amino acid sequence in common. Cross-reacting peptides were
Michael J. Atkinson; Harald J�ppner; Bettina Niepel; Monika Casaretto; Helmut Zahn; Rolf-Dieter Hesch
The Neuroendocrine Functions of the Parathyroid Hormone 2 Receptor
The G-protein coupled parathyroid hormone 2 receptor (PTH2R) is concentrated in endocrine and limbic regions in the forebrain. Its endogenous ligand, tuberoinfundibular peptide of 39 residues (TIP39), is synthesized in only two brain regions, within the posterior thalamus and the lateral pons. TIP39-expressing neurons have a widespread projection pattern, which matches the PTH2R distribution in the brain. Neuroendocrine centers including the preoptic area, the periventricular, paraventricular, and arcuate nuclei contain the highest density of PTH2R-positive networks. The administration of TIP39 and an antagonist of the PTH2R as well as the investigation of mice that lack functional TIP39 and PTH2R revealed the involvement of the PTH2R in a variety of neural and neuroendocrine functions. TIP39 acting via the PTH2R modulates several aspects of the stress response. It evokes corticosterone release by activating corticotropin-releasing hormone-containing neurons in the hypothalamic paraventricular nucleus. Block of TIP39 signaling elevates the anxiety state of animals and their fear response, and increases stress-induced analgesia. TIP39 has also been suggested to affect the release of additional pituitary hormones including arginine-vasopressin and growth hormone. A role of the TIP39-PTH2R system in thermoregulation was also identified. TIP39 may play a role in maintaining body temperature in a cold environment via descending excitatory pathways from the preoptic area. Anatomical and functional studies also implicated the TIP39-PTH2R system in nociceptive information processing. Finally, TIP39 induced in postpartum dams may play a role in the release of prolactin during lactation. Potential mechanisms leading to the activation of TIP39 neurons and how they influence the neuroendocrine system are also described. The unique TIP39-PTH2R neuromodulator system provides the possibility for developing drugs with a novel mechanism of action to control neuroendocrine disorders. PMID:23060860
Dobolyi, Arpad; Dimitrov, Eugene; Palkovits, Miklos; Usdin, Ted B.
Nmp4/CIZ Closes the Parathyroid Hormone Anabolic Window
Chronic degenerative diseases are increasing with the aging U.S. population. One consequence of this phenomenon is the need for long-term osteoporosis therapies. Parathyroid hormone (PTH), the only FDA-approved treatment that adds bone to the aged skeleton, loses its potency within two years of initial treatment but the mechanism regulating its limited �anabolic window� is unknown. We have discovered that disabling the nucleocytoplasmic shuttling transcription factor nuclear matrix protein 4/cas interacting zinc finger protein (Nmp4/CIZ) in mice extends the PTH bone-forming capacity. Nmp4 was discovered during our search for nuclear matrix transcription factors that couple this hormone�s impact on osteoblast cytoskeletal and nuclear organization with its anabolic capacity. CIZ was independently discovered as a protein that associates with the focal adhesion-associated mechanosensor p130Cas. The Nmp4/CIZ-knockout (KO) skeletal phenotype exhibits a modestly enhanced bone mineral density but manifests an exaggerated response to both PTH and to BMP2 and is resistant to disuse-induced bone loss. The cellular basis of the global Nmp4/CIZ-KO skeletal phenotype remains to be elucidated but may involve an expansion of the bone marrow osteoprogenitor population along with modestly enhanced osteoblast and osteoclast activities supporting anabolic bone turnover. As a shuttling Cys2His2 zinc finger protein, Nmp4/CIZ acts as a repressive transcription factor perhaps associated with epigenetic remodeling complexes, but the functional significance of its interaction with p130Cas is not known. Despite numerous remaining questions, Nmp4/CIZ provides insights into how the anabolic window is regulated, and itself may provide an adjuvant therapy target for the treatment of osteoporosis by extending PTH anabolic efficacy. PMID:23140162
Bidwell, Joseph P.; Childress, Paul; Alvarez, Marta B.; Hood, Mark; He, Yongzheng; Pavalko, Fredrick M.; Kacena, Melissa A.; Yang, Feng-Chun
Recent evidence links osteoporosis, a disease of bone remodeling, to changes in the dynamics of parathyroid hormone secretion. We use nonlinear and linear time series prediction to characterize the secretory dynamics of parathyroid hormone in both healthy human subjects and patients with osteoporosis. Osteoporotic patients appear to lack the periods of high predictability found in normal humans. Our results may provide an explanation for why an intermittent administration of parathyroid hormone is effective in restoring bone mass in osteoporotic patients. Images PMID:7769133
Prank, K; Nowlan, S J; Harms, H M; Kloppstech, M; Brabant, G; Hesch, R D; Sejnowski, T J
Parathyroid Hormone Mediates Hematopoietic Cell Expansion through Interleukin-6
Parathyroid hormone (PTH) stimulates hematopoietic cells through mechanisms of action that remain elusive. Interleukin-6 (IL-6) is upregulated by PTH and stimulates hematopoiesis. The purpose of this investigation was to identify actions of PTH and IL-6 in hematopoietic cell expansion. Bone marrow cultures from C57B6 mice were treated with fms-like tyrosine kinase-3 ligand (Flt-3L), PTH, Flt-3L plus PTH, or vehicle control. Flt-3L alone increased adherent and non-adherent cells. PTH did not directly impact hematopoietic or osteoclastic cells but acted in concert with Flt-3L to further increase cell numbers. Flt-3L alone stimulated proliferation, while PTH combined with Flt-3L decreased apoptosis. Flt-3L increased blasts early in culture, and later increased CD45+ and CD11b+ cells. In parallel experiments, IL-6 acted additively with Flt-3L to increase cell numbers and IL-6-deficient bone marrow cultures (compared to wildtype controls) but failed to amplify in response to Flt-3L and PTH, suggesting that IL-6 mediated the PTH effect. In vivo, PTH increased Lin- Sca-1+c-Kit+ (LSK) hematopoietic progenitor cells after PTH treatment in wildtype mice, but failed to increase LSKs in IL-6-deficient mice. In conclusion, PTH acts with Flt-3L to maintain hematopoietic cells by limiting apoptosis. IL-6 is a critical mediator of bone marrow cell expansion and is responsible for PTH actions in hematopoietic cell expansion. PMID:21048959
Pirih, Flavia Q.; Michalski, Megan N.; Cho, Sun W.; Koh, Amy J.; Berry, Janice E.; Ghaname, Eduardo; Kamarajan, Pachiyappan; Bonnelye, Edith; Ross, Charles W.; Kapila, Yvonne L.; Jurdic, Pierre; McCauley, Laurie K.
Parathyroid hormone is not an inhibitor of lipoprotein lipase activity.
The reduced lipoprotein lipase (LPL) activities in uraemia are reflected by increased serum triglyceride concentrations and reduced HDL cholesterol concentrations. Both hyperparathyroidism and circulating inhibitor(s) of LPL have been associated with the disturbances of lipid metabolism in uraemia. The aim of the present study was to investigate if parathyroid hormone (PTH) had an inhibitory effect on LPL activity. Plasma post-heparin LPL activities, plasma LPL inhibitory activities, serum PTHintact and serum PTHC-terminal concentrations were analysed in 20 patients on haemodialysis and 20 healthy controls. The effects of purified, human PTHintact and a carboxyterminal fragment of PTH (PTH39-84) on LPL activities in post-heparin plasma from healthy individuals and on the enzyme activity of purified, bovine milk LPL, activated with apolipoprotein CII, were studied. Patients had significantly higher plasma LPL inhibitory activities than controls, but there was no correlation between plasma LPL inhibitory activities and serum PTH concentrations. Neither PTHintact nor PTH39-84 had a significant effect on LPL activities in vitro. Thus there was no evidence of a direct inhibition of LPL activity by PTH under the present in-vivo or in-vitro conditions. PMID:7870347
Arnadottir, M; Nilsson-Ehle, P
Parathyroid hormone suppresses osteoblast apoptosis by augmenting DNA repair
Daily injection of parathyroid hormone (PTH) is a clinically approved treatment for osteoporosis. It suppresses apoptosis of bone forming osteoblasts although its exact anti-apoptotic mechanism(s) is incompletely understood. In this study, PTH treatment of cultured osteoblasts blocked the pro-apoptotic effects of serum withdrawal and nutrient deprivation; hydrogen peroxide induced oxidative stress, and UV irradiation. We hypothesized that PTH might suppress osteoblast apoptosis by enhancing DNA repair. Evidence is provided showing that post-confluent, non-proliferating osteoblasts treated with PTH exhibited a protein kinase A-mediated activation of two proteins that regulate DNA repair processes (proliferating cell nuclear antigen and forkhead box transcription factor 3a) as well as a suppression of the pro-apoptotic growth arrest and DNA damage protein 153. Additional proof of a connection between DNA damage and osteoblast apoptosis came from an unexpected finding whereby a majority of fixed PTH-treated osteoblasts scored weakly positive for Terminal Deoxynucleotidyl dUTP Nick-End Labeling (TUNEL), even though similar cultures were determined to be viable via a trypsin replating strategy. TUNEL identifies DNA excision repair, not just apoptotic DNA fragmentation, and the most likely explanation of these TUNEL results is that PTH's activation of DNA repair processes would permit nucleotide incorporation as a result of enhanced excision repair. This explanation was confirmed by an enhanced incorporation of bromodeoxyuridine in PTH-treated cells even though a majority of the cell population was determined to be non-replicating. An augmentation of DNA repair by PTH is an unreported finding, and provides an additional explanation for its anti-apoptotic mechanism(s). PMID:19450716
Schnoke, Matthew; Midura, Sharon B.; Midura, Ronald J.
Increase in the serum parathyroid hormone level during a bisphosphonate drug holiday.
After discontinuation of bisphosphonate therapy, an antiresorptive effect and antifracture protection persist for an undefined period. Patients are encouraged to continue calcium and vitamin D supplementation, during a bisphosphonate drug holiday. However, assessment of adequate calcium intake during the bisphosphonate drug holiday is difficult. Therefore, we measured the serum intact parathyroid hormone (PTH) level as a surrogate marker. A premenopausal woman discontinued bisphosphonate therapy, after 7.5 years of treatment. Two months later, blood calcium and phosphorus levels were normal, serum 25-hydroxyvitamin D level was 31.3 ng/mL, but serum PTH level had increased to 94.9 pg/mL. The elemental calcium supplement dose was increased to 600 mg/day, with no change in the cholecalciferol dose (400 IU). Her serum PTH levels decreased to 49.1 after 4 months and 32.9 pg/mL after 5 months. The serum PTH level may be helpful in assessing adequate calcium intake during a bisphosphonate drug holiday. PMID:25247160
Song, Yoon Kyung; Kim, Jeong Min; Park, Sun Jin; Lee, Seong-Kyu
Evidence for Skeletal Resistance to Parathyroid Hormone in Magnesium Deficiency
Hypocalcemia during magnesium (Mg) depletion has been well described, but the precise mechanism(s) responsible for its occurrence is not yet fully understood. The hypocalcemia has been ascribed to decreased parathyroid hormone (PTH) secretion as well as skeletal resistance to PTH. Whereas the former is well established, controversy exists as to whether or not Mg depletion results in skeletal resistance to PTH. These studies examine the skeletal response to PTH in normal dogs and dogs fed a Mg-free diet for 4-6 mo. Isolated tibia from normal (serum Mg 1.83�0.1 mg/100 ml) and experimental dogs (serum Mg 1.34�0.15 mg/100 ml) were perfused with Krebs-Henseleit buffer during a constant infusion of 3 ng/ml of synthetic bovine PTH 1-34 (syn b-PTH 1-34). The arteriovenous (A-V) difference for immunoreactive PTH (iPTH) across seven normal bones was 37.5�3%. In contrast, the A-V difference for iPTH was markedly depressed to 10.1�1% across seven bones from Mg-depleted dogs. These findings correlated well with a biological effect (cyclic AMP [cAMP] production) of syn b-PTH 1-34 on bone. In control bones, cAMP production rose from a basal level of 5.8�0.2 to 17.5�0.7 pmol/min after syn b-PTH 1-34 infusion. In experimental bones, basal cAMP production was significantly lower than in controls, 4.5�0.1 pmol/min, and increased to only 7.1�0.4 pmol/min after syn b-PTH 1-34 infusion. Even when PTH concentrations were increased to 20 ng/ml, cAMP production by experimental bones was lower than in control bones perfused with 3 ng/ml. Histological examination of bones from Mg-deficient dogs showed a picture compatible with skeletal inactivity. These studies demonstrate decreased uptake of iPTH and diminished cAMP production by bone, which indicates skeletal resistance to PTH in chronic Mg deficiency. Images PMID:227929
Freitag, Jeffrey J.; Martin, Kevin J.; Conrades, Mary B.; Bellorin-Font, Ezequiel; Teitelbaum, Steven; Klahr, Saulo; Slatopolsky, Eduardo
The acute response of parathyroid hormone to perturbations in serum ionized calcium ([Ca(2+)]) is physiologically complex, and poorly understood. The literature provides numerous observations of quantitative and qualitative descriptions of parathyroid hormone (PTH) dynamics. We present a physiologically based mathematical model of PTH secretion constructed from mechanisms suggested in the literature, and validated against complex [Ca(2+)] clamping protocols from human data. The model is based on two assumptions. The first is that secretion is a fraction of cellular reserves, with the fraction being determined by the kinetics of [Ca(2+)] with its receptor. The second is that there are multiple distinct populations of parathyroid cells, with different secretory parameters. The steady state and transient PTH secretion responses of the model are in agreement with human experimental PTH responses to different hypocalcemia and hypercalcemia stimuli. This mathematical model suggests that a population of secreting cells is responsible for the PTH secretory dynamics observed experimentally. PMID:24744900
Pruett, William A; Hester, Robert L
Abstract The acute response of parathyroid hormone to perturbations in serum ionized calcium ([Ca2+]) is physiologically complex, and poorly understood. The literature provides numerous observations of quantitative and qualitative descriptions of parathyroid hormone (PTH) dynamics. We present a physiologically based mathematical model of PTH secretion constructed from mechanisms suggested in the literature, and validated against complex [Ca2+] clamping protocols from human data. The model is based on two assumptions. The first is that secretion is a fraction of cellular reserves, with the fraction being determined by the kinetics of [Ca2+] with its receptor. The second is that there are multiple distinct populations of parathyroid cells, with different secretory parameters. The steady state and transient PTH secretion responses of the model are in agreement with human experimental PTH responses to different hypocalcemia and hypercalcemia stimuli. This mathematical model suggests that a population of secreting cells is responsible for the PTH secretory dynamics observed experimentally. PMID:24744900
Pruett, William A.; Hester, Robert L.
Recent observations indicate that in thyroparathyroidectomized (TPTX) rats fed a low (0.2 g/100 g) phosphorus diet, the tubular phosphaturic response to parathyroid hormone (PTH) remains markedly blunted even when it is assessed at normal or high plasma concentration and filtered load of inorganic phosphate (Pi). Because 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] decreases the tubular capacity to reabsorb Pi when chronically administered to TPTX rats, we have studied whether this vitamin D3 metabolite could specifically increase the phosphaturic response to PTH in phosphate-deprived animals. The results show that in Vitamin D-replete TPTX rats fed a low (0.2 g/100 g) phosphorus diet, 1,25(OH)2D3 (2 � 13 pmol/d i.p. for 7 d) markedly enhanced the acute tubular phosphaturic response to PTH (2.5 IU/h i.v.) without affecting the action of the peptide hormone on Ca reabsorption and cyclic-3?,5?-AMP excretion. The influence of 1,25(OH)2D3 on the phosphaturic response to PTH could not be ascribed to an increased plasma concentration and(or) filtered load of Pi during the administration of the peptide hormone. However, it could be, at least in part, related to the elevation in the basal level of plasma Pi which was observed in the 1,25(OH)2D3-treated animals. The results also indicate that 1,25(OH)2D3 significantly enhanced the calcemic response to PTH, which was blunted in these conditions of phosphate deprivation. Unlike 1,25-(OH)2D3, 25-hydroxyvitamin D3 did not unmask the phosphaturic effect of PTH in phosphate-depleted animals, even when given in doses 100 times larger. Thus, 1,25(OH)2D3 displays a selective and powerful activity in preventing the occurrence of tubular resistance to the phosphaturic action of PTH during Pi depletion. This finding suggests the existence of an important interaction between dietary Pi, 1,25(OH)2D3, and PTH in the homeostasis of phosphate. PMID:34630
Gloor, H. J.; Bonjour, J-P.; Caverzasio, J.; Fleisch, H.
Direct in vivo assessment of parathyroid hormone-calcium relationship curve in renal patients
Direct in vivo assessment of parathyroid hormone-calcium relation curve in renal patients. Secondary hyperparathyroidism (SHP) is a well documented finding even in the early stages of chronic renal failure (CRF). A sigmoidal relationship, fitting a four parameter model, links PTH secretion rate and calcium concentration changes. To our knowledge, PTH secretory parameters have only been studied in uremic patients who
Piergiorgio Messa; Clotilde Vallone; Giuseppe Mioni; Onelio Geatti; Daniela Turrin; Natalina Passoni; Aldo Cruciatti
Objective: To study associations between serum ionised calcium, serum parathyroid hormone (PTH) and blood pressure. Design: A population based, cross-sectional study was used. Methods: Blood pressure, body mass index, serum ionised calcium and serum PTH were measured in 460 males and 486 females in the Troms� study in 1994\\/1995. None were on medication for hypertension. The data were analysed with
Rolf Jorde; Kaare H B�naa; Johan Sundsfjord
DLC1-dependent parathyroid hormone-like hormone inhibition suppresses breast cancer bone metastasis
Bone metastasis is a frequent complication of breast cancer that is often accelerated by TGF-? signaling; however, little is known about how the TGF-? pathway is regulated during bone metastasis. Here we report that deleted in liver cancer 1 (DLC1) is an important regulator of TGF-? responses and osteolytic metastasis of breast cancer cells. In murine models, breast cancer cells lacking DLC1 expression exhibited enhanced capabilities of bone metastasis. Knockdown of DLC1 in cancer cells promoted bone metastasis, leading to manifested osteolysis and accelerated death in mice, while DLC1 overexpression suppressed bone metastasis. Activation of Rho-ROCK signaling in the absence of DLC1 mediated SMAD3 linker region phosphorylation and TGF-?�induced expression of parathyroid hormone�like hormone (PTHLH), leading to osteoclast maturation for osteolytic colonization. Furthermore, pharmacological inhibition of Rho-ROCK effectively reduced PTHLH production and breast cancer bone metastasis in vitro and in vivo. Evaluation of clinical breast tumor samples revealed that reduced DLC1 expression was linked to elevated PTHLH expression and organ-specific metastasis to bone. Overall, our findings define a stroma-dependent paradigm of Rho signaling in cancer and implicate Rho�TGF-? crosstalk in osteolytic bone metastasis. PMID:24590291
Wang, Yufeng; Lei, Rong; Zhuang, Xueqian; Zhang, Ning; Pan, Hong; Li, Gang; Hu, Jing; Pan, Xiaoqi; Tao, Qian; Fu, Da; Xiao, Jianru; Chin, Y. Eugene; Kang, Yibin; Yang, Qifeng; Hu, Guohong
Mechanical unloading of bone causes an imbalance in bone formation and resorption leading to bone loss and increased fracture risk. Black bears (Ursus americanus) are inactive for up to six months during hibernation, yet bone mineral content and strength do not decrease with disuse or aging. To test whether hibernating bears have biological mechanisms to prevent disuse osteoporosis, we measured the serum concentrations of hormones and growth factors involved in bone metabolism and correlated them with the serum concentration of a bone formation marker (osteocalcin). Serum was obtained from black bears over a 7-month duration that included periods of activity and inactivity. Both resorption and formation markers increased during hibernation, suggesting high bone turnover occurred during inactivity. However, bone formation appeared to be balanced with bone resorption. The serum concentration of parathyroid hormone (PTH) was higher in the hibernation (P=0.35) and post-hibernation (P=0.006) seasons relative to pre-hibernation levels. Serum leptin was lower (P<0.004) post-hibernation relative to pre-hibernation and hibernation periods. Insulin-like growth factor I (IGF-I) decreased (P<0.0001) during hibernation relative to pre-hibernation and reached its highest value during remobilization. There was no difference (P=0.64) in 25-OH vitamin D between the three seasons. Serum osteocalcin (bone formation marker) was significantly correlated with PTH, but not with leptin, IGF-I or 25-OH vitamin D. Osteocalcin and PTH were positively correlated when samples from all seasons were pooled and when only hibernation samples were considered, raising the possibility that the anabolic actions of PTH help maintain bone formation to prevent disuse osteoporosis. Prostaglandin E(2) (PGE(2)) release from MC3T3 osteoblastic cells was significantly affected by treatment with bear serum from different seasons (i.e. hibernation versus active periods). The seasonal changes in PGE(2) release showed trends similar to the seasonal changes in serum IGF-I. Since both PGE(2) and IGF-I are associated with collagenous bone formation, it is possible that seasonal changes in a circulating factor influence IGF-I levels in vivo in bears and PGE(2) release in osteoblastic cells in vitro. The significant decrease in serum leptin following arousal from hibernation may promote bone formation during remobilization, assuming there is a similar decrease in intracerebroventricular leptin. These findings support the idea that seasonal changes in the concentration of circulating molecules help regulate bone formation activity and may be important for preventing disuse osteoporosis in bears. PMID:16621944
Donahue, Seth W; Galley, Sarah A; Vaughan, Michael R; Patterson-Buckendahl, Patricia; Demers, Laurence M; Vance, Josef L; McGee, Meghan E
Pregnancy invokes a doubling of intestinal calcium absorption whereas lactation programs skeletal resorption to provide calcium to milk. Postweaning bone formation restores the skeleton's bone mineral content (BMC), but the factors that regulate this are not established. We used Pth-null mice to test whether parathyroid hormone (PTH) is required for postweaning skeletal recovery. On a normal 1% calcium diet, wild-type (WT) and Pth-null mice each gained BMC during pregnancy, declined 15% to 18% below baseline during lactation, and restored the skeleton above baseline BMC within 14 days postweaning. A 2% calcium diet reduced the lactational decline in BMC without altering the gains achieved during pregnancy and postweaning. The hypocalcemia and hyperphosphatemia of Pth-null mice normalized during lactation and serum calcium remained normal during postweaning. Osteocalcin and propeptide of type 1 collagen (P1NP) each rose significantly after lactation to similar values in WT and Pth-null. Serum calcitriol increased fivefold during pregnancy in both genotypes whereas vitamin D binding protein levels were unchanged. Absence of PTH blocked a normal rise in fibroblast growth factor-23 (FGF23) during pregnancy despite high calcitriol. A 30-fold higher expression of Cyp27b1 in maternal kidneys versus placenta suggests that the pregnancy-related increase in calcitriol comes from the kidneys. Conversely, substantial placental expression of Cyp24a1 may contribute significantly to the metabolism of calcitriol. In conclusion, PTH is not required to upregulate renal expression of Cyp27b1 during pregnancy or to stimulate recovery from loss of BMC caused by lactation. A calcium-rich diet in rodents suppresses skeletal losses during lactation, unlike clinical trials that showed no effect of supplemental calcium on lactational decline in BMC. PMID:23505097
Kirby, Beth J; Ma, Yue; Martin, Heather M; Buckle Favaro, Kerri L; Karaplis, Andrew C; Kovacs, Christopher S
Validation of 1-hour post-thyroidectomy parathyroid hormone level in predicting hypocalcemia
Background Prior work by our group suggested that a single one hour post-thyroidectomy parathyroid hormone (1�hr PTH) level could accurately stratify patients into high and low risk groups for the development of hypocalcemia. This study looks to validate the safety and efficacy of a protocol based on a 1�hr PTH threshold of 12�pg/ml. Study design Retrospective analysis of consecutive cohort treated with standardized protocol. Methods One hundred and twenty five consecutive patients underwent total or completion thyroidectomy and their PTH level was drawn 1-hour post operatively. Based on our previous work, patients were stratified into either a low risk group (PTH?12�pg/ml) or a high risk group (PTH???12�pg/ml). Patients in the high risk group were immediately started on prophylactic calcium carbonate (5�10�g/d) and calcitriol (0.5-1.0 mcg/d). The outcomes were then reviewed focusing mainly on how many low risk patients developed hypocalcemia (false negative rate), and how many high risk patients failed prophylactic therapy. Results Thirty one patients (25%) were stratified as high risk, and 94 (75%) as low risk. Five (16%) of the high risk patients became hypocalcemic despite prophylactic therapy. Two of the low risk group became hypocalcemic, (negative predictive value?=?98%). None of the hypocalcemic patients had anything more than mild symptoms. Conclusions A single 1-hour post-thyroidectomy PTH level is a very useful way to stratify thyroidectomy patients into high and low risk groups for development of hypocalcemia. Early implementation of oral prophylactic calcium and vitamin D in the high risk patients is a very effective way to prevent serious hypocalcemia. Complex protocols requiring multiple calcium and PTH measurements are not required to guide post-thyroidectomy management. PMID:24476535
RenaGel�, a nonabsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone.Background.This multicenter, open-label, dose-titration study assessed the safety and efficacy of RenaGel�, a nonabsorbed calcium- and aluminum-free phosphate binder, in lowering serum phosphorus. Secondary outcomes were its effects on serum intact parathyroid hormone (iPTH) and serum lipids.Methods.Phosphate binders were discontinued during a two-week washout period. Patients whose
Primary hyperparathyroidism (PHPT) may lead to skeletal deformities, fractures and renal failure in symptomatic patients if untreated. We present a case of a 30-year-old woman presented with muscle weakness, weight loss, hypercalcaemia and a pathological fracture, eventually with rapidly progressive musculoskeletal disease. Subsequent biochemical, radiographic and scintigraphy findings were consistent with PHPT from an ectopic mediastinal adenoma, and concomitant vitamin D deficiency. The severe hypercalcaemia was adequately temporised with hydration, forced diuresis and intravenous bisphosphonates. Removal of the adenoma by video-assisted thoracoscopic surgery was contemplated; however, consent was withdrawn precluding histological confirmation. A review of literature shows the changing profiles of patients with PHPT, the uncommon occurrence of parathyroid adenomas in ectopic locations and possible association between severity of PHPT and vitamin D status. PMID:24632909
Garingarao, Carlo Jan P; Paz-Pacheco, Elizabeth; Jimeno, Cecilia A
N-Terminal Phosphorylation of Parathyroid Hormone (PTH) Abolishes Its Receptor Activity.
The parathyroid hormone (PTH) is an 84-residue peptide, which regulates the blood Ca(2+) level via GPCR binding and subsequent activation of intracellular signaling cascades. PTH is posttranslationally phosphorylated in the parathyroid glands; however, the functional significance of this processes is not well characterized. In the present study, mass spectrometric analysis revealed three sites of phosphorylation, and NMR spectroscopy assigned Ser1, Ser3, and Ser17 as modified sites. These sites are located at the N-terminus of the hormone, which is important for receptor recognition and activation. NMR shows further that the three phosphate groups remotely disturb the ?-helical propensity up to Ala36. An intracellular cAMP accumulation assay elucidated the biological significance of this phosphorylation because it ablated the PTH-mediated signaling. Our studies thus shed light on functional implications of phosphorylation at native PTH as an additional level of regulation. PMID:25158085
Kumar, Amit; Gopalswamy, Mohanraj; Wishart, Clare; Henze, Mathias; Eschen-Lippold, Lennart; Donnelly, Dan; Balbach, Jochen
Hypercalcemia in patients with cancer may reflect the synthesis and secretion into circulation of parathyroid hormone-related protein (PTHrP) produced by the tumor. In the present study, we have measured circulating PTHrP concentrations in healthy subjects and patients using a new immunoradiometric assay (IRMA) that is specific for the 1�86 amino acid sequence of molecule, and in plasma collected with protease
A. Segura Dom�nguez; M. A. Andrade Olivi�; T. Rodr�guez Sousa; M. L. Terr�n Alvarez; D. Rodr�guez Perez; R. Alvarez Novoa; R. G. V. Garc�a-Mayor
Bone density parathyroid hormone and 25-hydroxyvitamin D concentrations in middle aged women
OBJECTIVE--To examine the relation between bone density and indices of calcium metabolism including parathyroid hormone and 25-hydroxyvitamin D concentrations in middle aged women. DESIGN--A cross sectional study. SETTING AND SUBJECTS--138 women volunteers aged 45-65 with no known osteoporosis and unselected for disease status recruited for a dietary assessment study from the community using general practice registers. Volunteer rate was 20%.
K. T. Khaw; M. J. Sneyd; J. Compston
Summary��The effect of parathyroid hormone (PTH) on alkaline phosphatase activity was examined in confluent, serum-free primary cultures\\u000a of neonatal mouse calvarial cells. It was found that synthetic bPTH-(1-34) caused an increase in the specific activity of\\u000a skeletal alkaline phosphatase isoenzyme by 18 hours. Between 10 and 500 ng\\/ml, the mganitude of the change was directly related\\u000a to peptide concentration. The
John A. Yee
Parathyroid Hormone-Related Protein Purified from a Human Lung Cancer Cell Line
A protein with biological activities similar to parathyroid hormone (PTH) has been purified from serum-free culture medium obtained from a human lung cancer cell line (BEN). A major protein band of 18 kDa was obtained on NaDodSO4\\/polyacrylamide gels, with faint bands at 35 kDa and 67 kDa. Biological activity was associated only with the 18-kDa band. Amino acid sequence analysis
J. M. Moseley; M. Kubota; H. Diefenbach-Jagger; R. E. H. Wettenhall; B. E. Kemp; C. P. Rodda; P. R. Ebeling; P. J. Hudson; J. D. Zajac; T. J. Martin
Calcitonin and parathyroid hormone in newborn infants with fracture of the clavicle
Summary��Determinations of serum calcium (Ca), phosphorus (P), calcitonin (CT), and parathyroid hormone (PTH) were carried out in 36\\u000a full-term newborn infants with fracture of the clavicle (CF) and in 46 normal neonates (N). At the 6th hour of life the CF\\u000a neonates demonstrated lower serum Ca and higher serum CT in comparison with normal infants. In the hours following, no
Franco Bagnoli; Silvia Bruchi; Silvia Sardelli; Luigi Vispi; Giuseppe Buonocore; Franco Franchi; Rodolfo Bracci
After baseline studies, 21 patients with osteoporosis were treated with human parathyroid hormone fragment (PTH 1-34) given as once-daily subcutaneous injections for 6-24 months. The dose used did not cause hypercalcaemia even in the first few hours after injection. Calcium and phosphate balances improved in some patients, but there was no significant improvement in the group values. There were, however,
J Reeve; P J Meunier; J A Parsons; M Bernat; O L Bijvoet; P Courpron; C Edouard; L Klenerman; R M Neer; J C Renier; D Slovik; F J Vismans; J T Potts
Parathyroid hormone (PTH) dose dependently inhibits growth factor- and stress-induced osteoblast proliferation via in- activating mitogen-activated protein kinase (MAPK) signaling pathways. Osteoblasts have recently been shown to express MAPK phosphatase (MKP)-1, a dual-specific phosphatase inac- tivator of MAPK. Investigated was the role of MKPs in the PTH-induced attenuation of MAPK and Jun N-terminal kinase (JNK) signaling in osteoblast-like UMR106-01 cells.
Background: Minimally invasive parathyroidectomy (MIP) is the preferred operation for patients with primary hyperparathyroidism (HPT) and positive preoperative imaging. This non-randomized case series assessed the long-term results of MIP performed without the use of intraoperative parathyroid hormone (ioPTH) monitoring. Methods: The study involved prospective collection of demographic, biochemical and operative details on a consecutive, unselected cohort of 298 patients who
R. Mihai; F. F. Palazzo; F. V. Gleeson; G. P. Sadler
The sidedness (apical vs basolateral) of the inhibitory of phosphate (Pi) transport by parathyroid hormone (PTH) was investigated in opossum kidney (OK)-cell monolayers grown on permeant support. PTH was found to regulate the activity of only the apical Na\\/Pi cotransporter, having no effect on the basolateral transport systems. Transport inhibition was approximately 100-fold more sensitive to apical PTH application (Kd:
Stephan J. Reshkin; Judith Forgo; Heini Murer
Summary��The effects of two different glucocorticoids, prednisone and deflazacort, (an oxazoline derivative of prednisolone) on bone\\u000a metabolism were analyzed in 10 patients with disorders that required glucocorticoid therapy. Significant elevations in blood\\u000a immunoreactive parathyroid hormone, alkaline phosphatase and urinary calcium, phosphate, hydroxyproline and nephrogenous cyclic\\u000a AMP were observed during prednisone therapy in addition to an increase in the exchangeable calcium
C. Gennari; B. Imbimbo; M. Montagnani; M. Bernini; P. Nardi; L. V. Avioli
The mechanisms by which parathyroid hormone (PTH) produces anemia are unclear. Parathyroid hormone secretion is regulated by the extracellular Ca2+ -sensing receptor. We investigated the effects of ablating PTH on hematological indices and erythrocytes volume regulation in wild-type, PTH-null, and Ca2+ -sensing receptor-null/PTH-null mice. The erythrocyte parameters were measured in whole mouse blood, and volume regulatory systems were determined by plasma membrane K+ fluxes, and osmotic fragility was measured by hemoglobin determination at varying osmolarities. We observed that the absence of PTH significantly increases mean erythrocyte volume and reticulocyte counts, while decreasing erythrocyte counts, hemoglobin, hematocrit, and mean corpuscular hemoglobin concentration. These changes were accompanied by increases in erythrocyte cation content, a denser cell population, and increased K+ permeability, which were in part mediated by activation of the K+ /Cl- cotransporter and Gardos channel. In addition we observed that erythrocyte osmotic fragility in PTH-null compared with wild-type mice was enhanced. When Ca2+ -sensing receptor gene was deleted on the background of PTH-null mice, we observed that several of the alterations in erythrocyte parameters of PTH-null mice were largely rescued, particularly those related to erythrocyte volume, K+ fluxes and osmotic fragility, and became similar to those observed in wild-type mice. Our results demonstrate that Ca2+ -sensing receptor and parathyroid hormone are functionally coupled to maintain erythrocyte homeostasis. PMID:23528155
Romero, Jose R; Youte, Rodeler; Brown, Edward M; Pollak, Martin R; Goltzman, David; Karaplis, Andrew; Pong, Lie-Chin; Chien, Lawrence; Chattopadhyay, Naibedya; Rivera, Alicia
Cinacalcet HCl, an allosteric modulator of the calcium-sensing receptor (CaR), has recently been approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, due to its suppressive effect on parathyroid hormone (PTH) secretion. Although cinacalcet's effects in patients with primary and secondary hyperparathyroidism have been reported, the crucial relationship between the effect of calcimimetics and
Takehisa Kawata; Yasuo Imanishi; Keisuke Kobayashi; Takao Kenko; Michihito Wada; Eiji Ishimura; Takami Miki; Nobuo Nagano; Masaaki Inaba; Andrew Arnold; Yoshiki Nishizawa
NASA Technical Reports Server (NTRS)
Parathyroid hormone (PTH) plays a central role in regulation of calcium metabolism. For example, excessive or inappropriate production of PTH or the related hormone, parathyroid hormone related protein (PTHrP), accounts for the majority of the causes of hypercalcemia. Both hormones act through the same receptor on the osteoblast to elicit enhanced bone resorption by the osteoclast. Thus, the osteoblast mediates the effect of PTH in the resorption process. In this process, PTH causes a change in the function and phenotype of the osteoblast from a cell involved in bone formation to one directing the process of bone resorption. In response to PTH, the osteoblast decreases collagen, alkaline phosphatase, and osteopontin expression and increases production of osteocalcin, cytokines, and neutral proteases. Many of these changes have been shown to be due to effects on mRNA abundance through either transcriptional or post-transcriptional mechanisms. However, the signal transduction pathway for the hormone to cause these changes is not completely elucidated in any case. Binding of PTH and PTHrP to their common receptor has been shown to result in activation of protein kinases A and C and increases in intracellular calcium. The latter has not been implicated in any changes in mRNA of osteoblastic genes. On the other hand activation of PKA can mimic all the effects of PTH; protein kinase C may be involved in some responses. We will discuss possible mechanisms linking PKA and PKC activation to changes in gene expression, particularly at the nuclear level.
Partridge, N. C.; Bloch, S. R.; Pearman, A. T.
Feline parathyroid hormone: validation of hormonal assays and dynamics of secretion.
Validated assays for quantification of intact parathyroid hormone (I-PTH) are no longer available. Moreover, the third-generation PTH assay that only detects the whole PTH molecule (W-PTH) has never been tested in cats. The work presented here is aimed to validate a commercially available assay for measurement of I-PTH and W-PTH in cats and to study the dynamics of PTH secretion in healthy cats. Our results show that both assays are reliable for the measurement of feline PTH. In healthy adult cats W-PTH concentration (15.1 � 1.6 pg/mL) was greater (P < 0.001) than I-PTH concentration (9.1 � 0.7 pg/mL). The dynamics of PTH secretion in response to changes in extracellular calcium (Ca(2+)) were investigated in 13 cats by studying PTH-Ca(2+) curves. PTH-Ca(2+) curves were obtained by intravenous infusion of disodium ethylenediaminetetraacetic acid and CaCl(2). PTH was measured using both I-PTH and W-PTH assays. During hypocalcemia a sigmoidal curve that was similar when measured with I-PTH or W-PTH was obtained. The maximal PTH concentration in response to hypocalcemia was greater with W-PTH (179.6 � 41.9 pg/mL) than with I-PTH (67.6 � 10.5 pg/mL; P = 0.01). However, hypercalcemia resulted in an equivalent PTH inhibition, with both assays yielding PTH concentrations as follows: W-PTH = 4.0 � 0.4 pg/mL and I-PTH = 4.9 � 0.3 pg/mL (NS). Parameters of the feline PTH-Ca(2+) curve are similar to what has been previously reported in dogs. PMID:22365655
Pineda, C; Aguilera-Tejero, E; Raya, A I; Diez, E; Rodriguez, M; Lopez, I
Nonlinear dynamics in pulsatile secretion of parathyroid hormone in normal human subjects
NASA Astrophysics Data System (ADS)
In many biological systems, information is transferred by hormonal ligands, and it is assumed that these hormonal signals encode developmental and regulatory programs in mammalian organisms. In contrast to the dogma of endocrine homeostasis, it could be shown that the biological information in hormonal networks is not only present as a constant hormone concentration in the circulation pool. Recently, it has become apparent that hormone pulses contribute to this hormonal pool, which modulates the responsiveness of receptors within the cell membrane by regulation of the receptor synthesis, movement within the membrane layer, coupling to signal transduction proteins and internalization. Phase space analysis of dynamic parathyroid hormone (PTH) secretion allowed the definition of a (in comparison to normal subjects) relatively quiet ``low dynamic'' secretory pattern in osteoporosis, and a ``high dynamic'' state in hyperparathyroidism. We now investigate whether this pulsatile secretion of PTH in healthy men exhibits characteristics of nonlinear determinism. Our findings suggest that this is conceivable, although on the basis of presently available data and techniques, no proof can be established. Nevertheless, pulsatile secretion of PTH might be a first example of nonlinear deterministic dynamics in an apparently irregular hormonal rhythm in human physiology.
Prank, Klaus; Harms, Heio; Brabant, Georg; Hesch, Rolf-Dieter; D�mmig, Matthias; Mitschke, Fedor
The Authors review the world literature on parathyroid cysts and report a case of this uncommon disease. The importance of an early pre-operative diagnosis by ultrasound, blood calcium level and parathyroid hormone assay with fine needle aspiration biopsy is pointed out. According to several surgeons, only the functioning parathyroid cysts require operation; needle aspiration may be appropriate therapy for the nonfunctioning ones. PMID:1758642
De Toma, G; Gabriele, R; Campli, M; Sgarzini, G; De Cesare, E
Small doses of parathyroid hormone and calcitonin were injected into thyroparathyroidectomized newborn rats to investigate the histological and chemical changes in bone surfaces and in mitochondrial granules of bone lining cells. Nondecalcified tissue specimens were observed under transmission electron microscope, electron probe X-ray microanalyzer, and microdiffraction after freeze substitution preparation of tibia shafts. Amorphous calcium phosphate, which appears as clusters and globules by this freeze substitution preparation, appears on the bone surfaces in a short time after the administration of a small dose of calcitonin. The Ca:PO4 ratio in the mitochondria of bone lining cells rises slightly with a small dose of parathyroid hormone and is reduced with a small dose of calcitonin. These data support the postulate that both parathyroid hormone and calcitonin act directly on bone lining cells in the process of influencing calcium concentrations of blood and temporarily storing calcium at bone surfaces.
Norimatsu, H.; Yamamoto, T.; Ozawa, H.; Talmage, R.V.
Response of parathyroid hormone to exercise and bone mineral density in adolescent female athletes
Background��This study investigates 1) the effects of amount of exercise on levels of serum parathyroid hormone (PTH) and calcium, and\\u000a 2) the relationship between PTH response and bone mineral density in adolescent female athletes.\\u000a \\u000a \\u000a \\u000a Subjects��Twenty-one female athletes on a top-ranked high school basketball team in Japan participated in a one-month intensive basketball\\u000a program. Subjects were divided into moderate-exercise and strenuous-exercise
Haruko Takada; Kaei WASHINO; Tadayuki Hanai; Hirotoshi Iwata
Generalized-ensemble simulations of the human parathyroid hormone fragment PTH(1-34)
NASA Astrophysics Data System (ADS)
A generalized-ensemble technique, multicanonical sampling, is used to study the folding of a 34-residue human parathyroid hormone fragment. An all-atom model of the peptide is employed and the protein-solvent interactions are approximated by an implicit solvent. Our results demonstrate that generalized-ensemble simulations are well suited to sample low-energy structures of such large polypeptides. Configurations with a root-mean-square deviation to the crystal structure of less than 1 � are found. Finally, we discuss limitations of our implicit solvent model.
Hansmann, Ulrich H. E.
Molecular recognition of parathyroid hormone by its G protein-coupled receptor
Parathyroid hormone (PTH) is central to calcium homeostasis and bone maintenance in vertebrates, and as such it has been used for treating osteoporosis. It acts primarily by binding to its receptor, PTH1R, a member of the class B G protein-coupled receptor (GPCR) family that also includes receptors for glucagon, calcitonin, and other therapeutically important peptide hormones. Despite considerable interest and much research, determining the structure of the receptor-hormone complex has been hindered by difficulties in purifying the receptor and obtaining diffraction-quality crystals. Here, we present a method for expression and purification of the extracellular domain (ECD) of human PTH1R engineered as a maltose-binding protein (MBP) fusion that readily crystallizes. The 1.95-{angstrom} structure of PTH bound to the MBP-PTH1R-ECD fusion reveals that PTH docks as an amphipathic helix into a central hydrophobic groove formed by a three-layer {alpha}-{beta}-{beta}{alpha} fold of the PTH1R ECD, resembling a hot dog in a bun. Conservation in the ECD scaffold and the helical structure of peptide hormones emphasizes this hot dog model as a general mechanism of hormone recognition common to class B GPCRs. Our findings reveal critical insights into PTH actions and provide a rational template for drug design that targets this hormone signaling pathway.
Pioszak, Augen A.; Xu, H. Eric (Van Andel)
We present a case with extremely high parathyroid hormone (PTH) concentrations in the order of hundred thousands accompanied by dermatological and hematological diseases. After several diagnostic interventions, no malignancy could be demonstrated except monoclonal gammopathy of unknown significance. The dermatological findings were taken to be manifestations of the hematological disease. Since the first serum intact PTH concentration of the patient was found to be higher than 2500 pg/ml, dilution study was performed and found to be 215,977 pg/ml. The high concentration of serum PTH was taken to be falsely high due to assay interference. This concentration was checked from three different paths; a test for linear dilution was performed, the test was repeated with another method and the sample was treated to remove or inhibit interfering substances. The results were compatible with endogenous antibody interference, presumed to be a result of monoclonal gammopathy. The extremely high PTH concentrations were not only due to assay interference, but also secondary hyperparathyroidism, which was evident by the decrease in PTH concentrations with calcium and vitamin D treatments. PMID:22906636
Tanriover, Mine Durusu; Portakal, Oytun; Hapa, Asli; Tekinel, Yasemin; Dagdelen, Selcuk; Buyukasik, Yahya; Arici, Mustafa
Levels of parathyroid hormone and calcitonin in serum among atomic bomb survivors
To examines the potential causes of increased levels of calcium in serum with increasing dose of atomic bomb radiation, which was obtained from the previous preliminary analysis, levels of parathyroid hormone (PTH) and calcitonin in serum were examined among 1459 subjects in Hiroshima and Nagasaki. A significant effect of radiation on levels of calcium, PTH and calcitonin in serum was found, even after patients with hyperparathyroidism were excluded. The level of calcium in serum increased with radiation dose; this can be explained partly by the increase in the level of PTH with radiation dose. However, the dose effect on calcium remained even after adjustment for PTH, calcitonin and confounding factors such as renal function, serum albumin level and medication. Parathyroid hormone increased initially by 6.8% per gray, but the dose response leveled off after about 1 Gy. The level of calcitonin increased with radiation dose, probably in part due to feedback mechanisms stimulated by the increase in calcium. However, after adjustment for the level of calcium, the increase in the level of calcitonin with dose was still found. Although the etiological mechanisms of the effect of radiation on serum levels of calcium, PTH and calcitonin are unclear, radiation exposure may affect secretion of PTH and calcitonin and regulation of calcium a long time after atomic bomb exposure. 21 refs., 3 figs., 6 tabs.
Fujiwara, Saeko; Yokoyama, Naokata; Sasaki, Hideo; Kodama, Kazunori; Sposto, R.; Shimaoka, Katsutaro [Radiation Effects Research Foundation (Japan); Shiraki, Mastaka [Tokyo Metropolitan Geriatric Hospital (Japan)
ALX 111 [parathyroid hormone (1-84) - NPS Allelix, recombinant human parathyroid hormone, rhPTH (1-84), PREOS] is a full-length, recombinant human parathyroid hormone. It has potential as an anti-osteoporotic agent, due to its properties as a bone formation stimulant. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It has been recommended that ALX 111 should be given for 1 to 2 years and may be given in combination with an antiresorptive agent, such as estrogen or a bisphosphonate. In December 1999, Allelix Biopharmaceuticals merged with NPS Pharmaceuticals. This combined company is operating as NPS Pharmaceuticals in the US and as NPS Allelix in Canada. The merger has enabled a phase III study of ALX 111 to begin in the US, Europe and South America. NPS harmaceuticals has signed an agreement with Bio-Imaging Technologies, which will provide all image handling and analysis for this trial. Until 1994, Allelix Biopharmaceuticals and Glaxo in Canada were involved in a joint venture to investigate the efficacy of ALX 111 in osteoporosis. Allelix was subsequently, until September 1998, collaborating with Astra of Sweden in developing ALX 111. Astra had acquired exclusive worldwide rights to ALX 111 and was responsible for development of the agent. However, Astra returned all rights to ALX 111 to Allelix as a result of its merger with Zeneca to form AstraZeneca. In December 1999, Allelix Biopharmaceuticals merged with NPS Pharmaceuticals. This combined company is operating as NPS Pharmaceuticals in the US and as NPS Allelix in Canada. The merger has enabled a phase III study of ALX 111 to begin in the US, Europe and South America. The phase III trial of ALX 111 for the treatment of osteoporosis has completed patient enrolment, and phase II trials have been completed in Canada and the Netherlands. The 18-month, phase III, multicentre, placebo-controlled trial (Treatment of Osteoporosis with Parathyroid Hormone; TOP) has been designed to assess the bone-building and fracture-reducing potential of the drug, and over 2600 postmenopausal women with osteoporosis who have not received previous drug therapy for osteoporosis have been enrolled. Treatment will be completed in September 2003, but more than 75% of patients enrolled in the TOP study have chosen to enrol in an Open Label Extension Study (OLES), which allows for a total treatment period of up to 24 months. NPS Pharmaceuticals has signed an agreement with Bio-Imaging Technologies, which will provide all image handling and analysis for this trial. In September 2002, NPS Pharmaceuticals announced that it has met its patient enrolment target (n > 150) for its POWER (PTH for Osteoporotic Women on Estrogen Replacement) study; a 24-month phase III trial initiated in Europe in November 2001. In this trial, women with osteoporosis receive SC injections of ALX 111 or placebo, in combination with their existing hormone replacement therapies, to test the bone building potential of the drug. In addition to the POWER study, a clinical trial sponsored by the National Institutes of Health (NIH) is being conducted to evaluate the potential of ALX 111 to build bone in combination with another osteoporosis medication. The 'PaTH' study (PTH/alendronate) is designed to assess the effect of various combinations and sequential uses of ALX 111 and Merck's Fosamax, a drug for slowing the loss of bone due to osteoporosis. The PaTH study, initiated in May 2000 and scheduled to conclude in September 2003, involved 238 patients with postmenopausal osteoporosis. It is thought that alendronic acid and ALX 111, when administered in combination, may act in an additive manner to treat osteoporosis because they act in different ways; alendronic acid acts to inhibit resorption and ALX 111 speeds up bone formation and resorption, with a net increase in formation. Results of this study are still being analysed but preliminary results appear to be positive. The effect of ALX 111 on bone cell cultures underare still being analysed but p
Previous studies have shown that parathyroid hormone (PTH) monotherapy and cotherapy with estrogen or risedronate augment vertebral bone mass and bone strength in young, ovariectomized (OVX) rats. The current study was designed to determine whether PTH has similar bone anabolic effects in aged OVX rats at a much later stage of estrogen depletion. Female Sprague Dawley rats were subjected to
M. Li; Li. Mosekilde; C. H. S�gaard; J. S. Thomsen; T. J. Wronski
With the markedly reduced usage of aluminum salts in renal failure, parathyroid hormone (PTH) has become the major determinant of currently seen bone disease. Clinicians now must consider what PTH level should be sought. Too low a level may lead to the aplastic bone lesion (low turnover bone), and too high a level may cause osteitis fibrosa. Furthermore, conventional normal
Mei Wang; Gavril Hercz; Donald J. Sherrard; Norma A. Maloney; Gino V. Segre; York Pei
Use of hormonal contraceptives (HC) may influence total plasma concentrations of vitamin D metabolites. A likely cause is an increased synthesis of vitamin D binding protein (VDBP). Discrepant results are reported on whether the use of HC affects free concentrations of vitamin D metabolites. Aim: In a cross-sectional study, plasma concentrations of vitamin D metabolites, VDBP, and the calculated free vitamin D index in users and non-users of HC were compared and markers of calcium and bone metabolism investigated. Results: 75 Caucasian women aged 25�35 years were included during winter season. Compared with non-users (n = 23), users of HC (n = 52) had significantly higher plasma concentrations of 25-hydroxyvitamin D (25OHD) (median 84 interquartile range: [67-111] vs. 70 [47-83] nmol/L, p = 0.01), 1,25-dihydroxyvitamin D (1,25(OH)2D) (198 [163-241] vs. 158 [123-183] pmol/L, p = 0.01) and VDBP (358 [260-432] vs. 271 [179-302] �g/mL, p < 0.001). However, the calculated free indices (FI-25OHD and FI-1,25(OH)2D) were not significantly different between groups (p > 0.10). There were no significant differences in indices of calcium homeostasis (plasma concentrations of calcium, parathyroid hormone, and calcitonin, p > 0.21) or bone metabolism (plasma bone specific alkaline phosphatase, osteocalcin, and urinary NTX/creatinine ratio) between groups. In conclusion: Use of HC is associated with 13%�25% higher concentrations of total vitamin D metabolites and VDBP. This however is not reflected in indices of calcium or bone metabolism. Use of HC should be considered in the interpretation of plasma concentrations vitamin D metabolites. PMID:24013463
M?ller, Ulla K.; vi? Streym, Susanna; Jensen, Lars T.; Mosekilde, Leif; Schoenmakers, Inez; Nigdikar, Shailja; Rejnmark, Lars
1 Agents known to delay absorption from a subcutaneous site were tested in chicks for their ability to prolong the hypercalcaemic response to parathyroid hormone (PTH). 2 Polyvinylpyrrolidone was found to enhance the response but gelatine greatly reduced the 2 h hypercalcaemia. 3 The reduction by gelatine was reversed when the protease inhibitor aprotinin was added to the injection vehicle, and hypercalcaemia then persisted for more than 8 h. 4 Of other protease inhibitors studied, epsilon-aminocaproic acid was also found to enhance the hypercalcaemic response to subcutaneous PTH and its fragments but, unlike aprotinin, it was ineffective in the presence of gelatine. 5 By radioimmunoassay and bioassay respectively, it was confirmed that aprotinin raised circulating levels of PTH and also of another peptide hormone, calcitonin, injected subcutaneously. 6 Addition of calcium to the solutions injected subcutaneously abolished the hypercalcaemic response to PTH while injection of calcium and PTH simultaneously but at separate sites left the response unaltered. 7 The two protease inhibitors, epsilon-aminocaproic acid and aprotinin, each restored the response to subcutaneous PTH despite the presence of calcium at the injection site. 8 It was concluded that protease inhibitors injected subcutaneously with PTH and calcitonin in the chick reduced the rate of degradation of these hormones and that the proteases responsible for hormone degradation at the subcutaneous injection site may be released or activated by calcium ions. PMID:313228
Parsons, J. A.; Rafferty, B.; Stevenson, R. W.; Zanelli, J. M.
RESULTS: The incidence of vitamin A deficiency was 69%, vitamin K deficiency 68%, and vitamin D deficiency 63% by the fourth year after surgery. The incidence of vitamin E and zinc deficiency did not increase with time after surgery. The incidence of hypocalcemia increased from 15% to 48% over the study period with a corresponding increase in serum parathyroid hormone
Slater GH; Siegel N; Williams T; Barr D; Wolfe B; Dolan K
Original article Peculiarities of vitamin D and of the calcium
Original article Peculiarities of vitamin D and of the calcium and phosphate homeostatic system in the horse. The con- centrations of Ca, Pi, vitamin D metabolites, parathyroid hormone (PTH), the activity of the alkaline phosphatase (AP) and the concentration and binding properties of vitamin D binding pro- tein (DBP
Paris-Sud XI, Université de
Parathyroid hormone-dependent endocytosis of renal type IIc Na-Pi cotransporter.
Hereditary hypophosphatemic rickets with hypercalciuria results from mutations of the renal type IIc Na-P(i) cotransporter gene, suggesting that the type IIc transporter plays a prominent role in renal phosphate handling. The goal of the present study was to investigate the regulation of the type IIc Na-P(i) cotransporter by parathyroid hormone (PTH). Type IIc Na-P(i) cotransporter levels were markedly increased in thyroparathyroidectomized (TPTX) rats. Four hours after administration of PTH, type IIc transporter protein levels were markedly decreased in the apical membrane fraction but recovered to baseline levels at 24 h. Immunohistochemical analyses demonstrated the presence of the type IIc transporter in the apical membrane and subapical compartments in the proximal tubular cells in TPTX animals. After administration of PTH, the intensity of immunoreactive signals in apical and subapical type IIc transporter decreased in the renal proximal tubular cells in TPTX rats. Colchicine completely blocked the internalization of the type IIc transporter. In addition, leupeptin prevented the PTH-mediated degradation of the type IIa transporter in lysosomes but had no effect on PTH-mediated degradation of the lysosomal type IIc transporter. In PTH-treated TPTX rats, the internalization of the type IIc transporter occurred after administration of PTH(1-34) (PKA and PKC activator) or PTH(3-34) (PKC activator). Thus the present study demonstrated that PTH is a major hormonal regulator of the type IIc Na-P(i) cotransporter in renal proximal tubules. PMID:16985216
Segawa, Hiroko; Yamanaka, Setsuko; Onitsuka, Akemi; Tomoe, Yuka; Kuwahata, Masashi; Ito, Mikiko; Taketani, Yutaka; Miyamoto, Ken-ichi
Parathyroid hormone-sensitive adenylate cyclase system in plasma membranes of rat liver
Purified plasma membranes were prepared from normal rat livers. These membranes were unable to degrade parathyroid hormone (PTH), bovine PTH-(1 to 84) (bPTH-(1 to 84)), or bPTH-(1 to 34). The entire molecule bPTH-(1 to 84) caused a marked activation of adenylate cyclase (cAMP production increased over 5-fold), with half-maximal stimulation at 6.9 x 10/sup -8/ M. The amino-terminal fragment bPTH-(1 to 34) was equipotent but gave a smaller maximal cAMP production. The human (h) amino acid sequence, hPTH-(1 to 34) was only weakly effective at a concentration of 10/sup -5/ M. A similar species specificity was shown with crude rat renal cortical membranes. Of a variety of ligands, only glucagon and 10/sup -3/ M F/sup -/ were cyclase activators in these liver plasma membranes. Binding of (/sup 125/I)iodo-bPTH by these membranes was fairly extensive but showed a saturation of binding only at high hormone concentrations (> 10/sup -6/ M). Clearly, cleavage of the intact molecule PTH-(1 to 84) is not required for activation of the adenylate cyclase system of liver membranes. It appears that two rat tissues, liver and kidney, exhibit some species specificity in cyclase activation, i.e. the hPTH-(1 to 34) (Niall sequence) is inactive.
Neuman, W.F.; Schneider, N.
Previous results have shown that 1,25-dihydroxycholecalciferol [1,25(OH)2D3] enhances the synthesis of phosphatidylserine (PS) and suppresses the synthesis of phosphatidylethanolamine (PE) in osteoblast-like rat osteogenic sarcoma UMR 106 cells [Matsumoto, Kawanobe, Morita & Ogata (1985) J. Biol. Chem. 260, 13704-13709]. In the present study, the effect of parathyroid hormone (PTH) on phospholipid metabolism is examined by using these cells. Treatment of UMR 106 cells with human PTH-(1-34)-peptide suppresses the synthesis of phosphatidylethanolamine in a dose- and time-dependent manner without affecting the synthesis of PS. The maximal effect on PE synthesis is obtained with 2.4 nM-human PTH-(1-34)-peptide when the cells are treated for 48 h or longer. In addition, when human PTH-(1-34)-peptide is added together with the maximal dose of 1,25(OH)2D3, there is a further decline in PE synthesis, whereas the stimulation of PS synthesis by 1,25(OH)2D3 is not altered. Because methylation of PE is suggested to affect hormone receptor-adenylate cyclase coupling, the observed change in PE metabolism by PTH and 1,25(OH)2D3 may be, at least in part, involved in the development of desensitization phenomenon to PTH in these cells. PMID:3019320
Matsumoto, T; Morita, K; Kawanobe, Y; Ogata, E
The application of artificial neural network (ANN) to predict outcome and explore potential relationships among clinical data is increasing being used in many clinical scenarios. The aim of this study was to validate whether an ANN is a useful tool for predicting the target range of plasma intact parathyroid hormone (iPTH) concentration in hemodialysis patients. An ANN was constructed with input variables collected retrospectively from an internal validation group (n = 129) of hemodialysis patients. Plasma iPTH was the dichotomous outcome variable, either target group (150 ng/L
Wang, Yuh-Feng; Hu, Tsung-Ming; Wu, Chia-Chao; Yu, Fu-Chiu; Fu, Chao-Ming; Lin, Shih-Hua; Huang, Wei-Hsin; Chiu, Jainn-Shiun
Observational studies in primary hyperaldosteronism suggest a positive relationship between aldosterone and parathyroid hormone (PTH); however, interventions to better characterize the physiological relationship between the renin-angiotensin-aldosterone system (RAAS) and PTH are needed. We evaluated the effect of individual RAAS components on PTH using 4 interventions in humans without primary hyperaldosteronism. PTH was measured before and after study (1) low-dose angiotensin II (Ang II) infusion (1 ng/kg per minute) and captopril administration (25 mg�1); study (2) high-dose Ang II infusion (3 ng/kg per minute); study (3) blinded crossover randomization to aldosterone infusion (0.7 �g/kg per hour) and vehicle; and study (4) blinded randomization to spironolactone (50 mg/daily) or placebo for 6 weeks. Infusion of Ang II at 1 ng/kg per minute acutely increased aldosterone (+148%) and PTH (+10.3%), whereas Ang II at 3 ng/kg per minute induced larger incremental changes in aldosterone (+241%) and PTH (+36%; P<0.01). Captopril acutely decreased aldosterone (-12%) and PTH (-9.7%; P<0.01). In contrast, aldosterone infusion robustly raised serum aldosterone (+892%) without modifying PTH. However, spironolactone therapy during 6 weeks modestly lowered PTH when compared with placebo (P<0.05). In vitro studies revealed the presence of Ang II type I and mineralocorticoid receptor mRNA and protein expression in normal and adenomatous human parathyroid tissues. We observed novel pleiotropic relationships between RAAS components and the regulation of PTH in individuals without primary hyperaldosteronism: the acute modulation of PTH by the RAAS seems to be mediated by Ang II, whereas the long-term influence of the RAAS on PTH may involve aldosterone. Future studies to evaluate the impact of RAAS inhibitors in treating PTH-mediated disorders are warranted. PMID:24191286
Brown, Jenifer M; Williams, Jonathan S; Luther, James M; Garg, Rajesh; Garza, Amanda E; Pojoga, Luminita H; Ruan, Daniel T; Williams, Gordon H; Adler, Gail K; Vaidya, Anand
The effect of parathyroid hormone (PTH) on blood lead (Pb) concentrations was observed preliminarily in three different situations. Of 342 healthy bus drivers with no unusual exposure to Pb, 25 drivers with the highest and 25 with the lowest blood Pb were compared for serum PTH concentrations. There was no association between blood Pb and serum PTH concentrations. Eight women with postmenopausal osteoporosis enrolled in an experimental protocol to increase bone mass received daily PTH (1-34 fragment) for 1 week, calcitonin for the next 2 weeks, and oral calcium for the subsequent 10 weeks. This cycle was repeated four times during the year. Initial blood Pb concentrations averaged 6.0 micrograms/dl (range 2.1-8.9). Mean blood Pb concentrations decreased by 1.7 micrograms/dl over 1 year of therapy. The confidence interval for this change excluded zero, the mean change was significantly different from the mean change for comparative population (P less than 0.050), and paired changes were statistically significant (P = 0.045). Lastly, a single subject with hyperparathyroid disease and no unusual exposures to lead demonstrated stabilized blood Pb concentrations that were 50% lower after removal of his hyperplastic parathyroid glands. These observations suggest that the effect of PTH on increasing bone turnover and releasing Pb into blood is not easily detected at low physiologic amounts of PTH, but that with pathologic increases of PTH in hyperparathyroid disease, elevation of blood Pb from bone or increased gastrointestinal absorption may be possible. Likewise, either bone building therapies (PTH + calcitonin + calcium) may move Pb from blood into bone or supplemental calcium may decrease Pb gastrointestinal absorption, thereby explaining the observed lower blood Pb concentrations.
Osterloh, J.D. (Univ. of California, San Francisco (USA))
NASA Astrophysics Data System (ADS)
Serum 25-hydroxyvitamin D3 [25(OH)D3] is produced in the skin in response to exposure to ultraviolet radiation, and is a good indicator of vitamin D nutritional status. The aim of this study was to determine summer/winter differences in serum 25(OH)D3 and parathyroid hormone (PTH) in Japanese women and how the summer and winter values are related. The subjects were 122 healthy Japanese women aged 45-81 years (average age: 65.7 years). They were medically examined twice, in September 1997 and February 1999. Serum 25(OH)D3 and intact PTH were determined by high-performance liquid chromatography and a two-site immunoradiometric assay respectively. Lifestyle information was obtained through an interview. The seasonal differences (winter minus summer) in 25(OH)D3 [?25(OH)D3] and intact PTH concentrations were -18.8 nmol/l (SD 19.2, P<0.0001) and 0.98pmol/l (SD 1.02, P<0.0001) respectively. The correlation coefficient between summer (x) and winter (y) 25(OH)D3 levels was 0.462 (P<0.0001), with a linearly fitted line of y=0.42x+26.4. This relationship was interpreted as subjects with higher summer 25(OH)D3 values having greater reductions in winter 25(OH)D3 concentrations. There were inter-individual differences in ?25(OH)D3, although the summer and winter 25(OH)D3 concentrations were well-correlated. Since ?25(OH)D3 was not associated with any of the lifestyle factors, seasonal differences in the 25(OH)D3 concentrations of an individual appeared to reflect her ability to produce 25(OH)D3 photochemically in the skin. Sun bathing would be a less effective means of attaining adequate vitamin D nutritional status in a person with a small seasonal difference in 25(OH)D3, i.e., one with a low 25(OH)D3 level.
Nakamura, K.; Nashimoto, Mitsue; Yamamoto, Masaharu
The objective of this systematic review was to examine the influence of treatments for postmenopausal osteoporosis (parathyroid\\u000a hormone [PTH], bisphosphonates, strontium ranelate, and denosumab) on bone quality and discuss the clinical implications.\\u000a Most bone-quality data for PTH is from teriparatide. Teriparatide results in a rapid increase in bone-formation markers, followed\\u000a by increases in bone-resorption markers, opening an �anabolic window,� a
S. J. Gallacher; T. Dixon
Summary��Available evidencein vitro andin vivo suggests that pharmacologic doses of isoproterenol stimulate the secretion of parathyroid hormone (PTH) and calcitonin (CT)\\u000a and propranolol inhibits secretion. However, the findings in man are either quite modest or inconsistent. In view of this\\u000a controversy, we examined the effects of isoproterenol, 0.15 �g intradermally (i.d.), dopamine, 5 �g\\/kg body weight over 60\\u000a min intravenously
Sol Epstein; Hunter Heath; Norman H. Bell
.�� This study was designed to determine the fate of new parathyroid hormone (PTH)-induced cortical bone after withdrawal of\\u000a PTH treatment, and to evaluate whether subsequent treatment with a bisphosphonate would influence this. Six groups of 21-month-old\\u000a rats were used: a baseline group killed at the beginning of the experiment, three groups injected with human PTH (1-34) (62\\u000a ?g\\/kg) daily
C. Ejersted; H. Oxlund; T. T. Andreassen
Effects of parathyroid hormone (1�34) on tibia in an adult rat model for chronic alcohol abuse
Chronic alcohol abuse is a risk factor for osteoporosis in men. Human recombinant parathyroid hormone (1�34) (PTH) therapy increases bone mass in patients with osteoporosis. The purpose of the present study was to determine whether PTH is effective in increasing bone formation and bone mass in a rat model for established osteopenia caused by chronic alcohol abuse. Eight-month-old male Sprague
Jean D. Sibonga; Urszula T. Iwaniec; Kristen L. Shogren; Clifford J. Rosen; Russell T. Turner
Parathyroid hormone-related protein (PTHrP) is a hypercalcemic factor in mammals. The PTHrP antigen has been localized in both bony and cartilaginous fish tissues. Sites of localization included gills, skin and kidney, organs involved in osmoregulation. Physiological and localization experiments were carried out in elasmobranchs to dissect PTHrP's possible role in osmoregulation. The effects of alterations in the external environment on
Melanie K Trivett; Terry I Walker; John G Clement; Pat M. W Ho; T. J Martin; Janine A Danks
Objectives. Parathyroid hormone�related protein (PTHrP) is a primary factor in the pathogenesis of malignancy-associated hypercalcemia. By alternative splicing, the human PTHrP gene can generate three different species of mRNA that encode three initial translational isoforms of 139, 173, and 141 amino acids. We recently reported that PTHrP was present in normal prostatic neuroendocrine cells and was overexpressed in prostate cancer
Guan Wu; Masatsugu Iwamura; P. Anthony Di Sant�agnese; Leonard J. Deftos; Abraham T. K. Cockett; Sten Gershagen
Highlights: Black-Right-Pointing-Pointer Different PTH administration exerts different effects on condylar chondrocyte. Black-Right-Pointing-Pointer Intermittent PTH administration suppresses condylar chondrocyte proliferation. Black-Right-Pointing-Pointer Continuous PTH administration maintains condylar chondrocyte proliferating. Black-Right-Pointing-Pointer Intermittent PTH administration enhances condylar chondrocyte differentiation. -- Abstract: Endochondral ossification is a complex process involving chondrogenesis and osteogenesis regulated by many hormones and growth factors. Parathyroid hormone (PTH), one of the key hormones regulating bone metabolism, promotes osteoblast differentiation and osteogenesis by intermittent administration, whereas continuous PTH administration inhibits bone formation. However, the effects of PTH on chondrocyte proliferation and differentiation are still unclear. In this study, intermittent PTH administration presented enhanced effects on condylar chondrocyte differentiation and bone formation, as demonstrated by increased mineral nodule formation and alkaline phosphatase (ALP) activity, up-regulated runt-related transcription factor 2 (RUNX2), ALP, collagen type X (COL10a1), collagen type I (COL1a1), osteocalcin (OCN), bone sialoprotein (BSP), bone morphogenetic protein 2 (BMP2) and osterix (OSX) mRNA and/or protein expression. On the contrary, continuous PTH administration promoted condylar chondrocyte proliferation and suppressed its differentiation, as demonstrated by up-regulated collagen type II (COL2a1) mRNA expression, reduced mineral nodule formation and down-regulated expression of the mRNAs and/or proteins mentioned above. Our data suggest that PTH can regulate condylar chondrocyte proliferation and differentiation, depending on the type of PTH administration. These results provide new insight into the effects of PTH on condylar chondrocytes and new evidence for using local PTH administration to cure mandibular asymmetry.
Liu, Qi; Wan, Qilong; Yang, Rongtao; Zhou, Haihua [The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079 (China)] [The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079 (China); Li, Zubing, E-mail: firstname.lastname@example.com [The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079 (China) [The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079 (China); Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079 (China)
Vitamin D and DBP: the free hormone hypothesis revisited.
The last five years have witnessed a remarkable renaissance in vitamin D research and a complete re-evaluation of its benefits to human health. Two key factors have catalyzed these changes. First, it now seems likely that localized, tissue-specific, conversion of 25-hydroxyvitamin D (25OHD) to 1,25-dihydroxyvitamin D (1,25(OH)2D) drives many of the newly recognized effects of vitamin D on human health. The second key factor concerns the ongoing discussion as to what constitutes adequate or optimal serum vitamin D (25OHD) status, with the possibility that vitamin D-deficiency is common to communities across the globe. These two concepts appear to be directly linked when low serum concentrations of 25OHD compromise intracrine generation of 1,25(OH)2D within target tissues. But, is this an over-simplification? Pro-hormone 25OHD is a lipophilic molecule that is transported in the circulation bound primarily to vitamin D binding protein (DBP). While the association between 25OHD and DBP is pivotal for renal handling of 25OHD and endocrine synthesis of 1,25(OH)2D, what is the role of DBP for extra-renal synthesis of 1,25(OH)2D? We hypothesize that binding to DBP impairs delivery of 25OHD to the vitamin D-activating enzyme 1?-hydroxylase in some target cells. Specifically, it is unbound, 'free' 25OHD that drives many of the non-classical actions of vitamin D. Levels of 'free' 25OHD are dependent on the concentration of DBP and alternative serum binding proteins such as albumin, but will also be influenced by variations in DBP binding affinity for specific vitamin D metabolites. The aim of this review will be to discuss the merits of 'free 25OHD' as an alternative marker of vitamin D status, particularly in the context of non-classical responses to vitamin D. This article is part of a Special Issue entitled '16th Vitamin D Workshop'. PMID:24095930
Chun, Rene F; Peercy, Bradford E; Orwoll, Eric S; Nielson, Carrie M; Adams, John S; Hewison, Martin
Effect of parathyroid hormone on early chondrogenic differentiation from mesenchymal stem cells
Background Treatment of articular cartilage injuries remains a difficult challenge due to the limited capacity for intrinsic repair. Mesenchymal stem cells (MSCs) can differentiate into chondrocytes under certain culture conditions. This study focused on the modulatory effects of parathyroid hormone (PTH) on chondrogenic differentiation from MSCs. Methods MSCs were treated with various concentrations of PTH under chondrogenic pellet culture condition. RNA was isolated for real-time polymerase chain reaction (PCR) and gene expressions of collagen type II ?1 chain (Col2a1), collagen type X ?1 chain, collagen type I ?1 chain, SRY-box9 (Sox9), and type 1 PTH/PTHrP receptor (PTH1R) were examined. Chondrogenic differentiation was also evaluated by histological findings. Results PTH had opposite effects on chondrogenesis, depending on the concentration. A low to moderate concentration of PTH promoted chondrogenic differentiation of MSCs with increased expression of Sox9, Col2a1, and PTH1R, whereas chondrogenesis of MSCs was inhibited rather than stimulated with a higher concentration of PTH. Conclusion This study provides insights into the modulatory effect of PTH on chondrogenic differentiation from MSCs and the therapeutic potential for cartilage regeneration. Based on clinical experience regarding the efficacy and safety of PTH for bone metabolism, PTH may also be useful clinically for cartilage repair. PMID:25079095
Intermittently administered parathyroid hormone [1-34] promotes tendon-bone healing in a rat model.
The objective of this study was to investigate whether intermittent administration of parathyroid hormone [1-34] (PTH[1-34]) promotes tendon-bone healing after anterior cruciate ligament (ACL) reconstruction in vivo. A rat model of ACL reconstruction with autograft was established at the left hind leg. Every day, injections of 60 ?g PTH[1-34]/kg subcutaneously were given to the PTH group rats (n = 10) for four weeks, and the controls (n = 10) received saline. The tendon-bone healing process was evaluated by micro-CT, biomechanical test, histological and immunohistochemical analyses. The effects of PTH[1-34] on serum chemistry, bone microarchitecture and expression of the PTH receptor (PTH1R) and osteocalcin were determined. Administration of PTH[1-34] significantly increased serum levels of calcium, alkaline phosphatase (AP), osteocalcin and tartrate-resistant acid phosphatase (TRAP). The expression of PTH1R on both osteocytes and chondrocyte-like cells at the tendon-bone interface was increased in the PTH group. PTH[1-34] also enhanced the thickness and microarchitecture of trabecular bone according to the micro-CT analysis. The results imply that systematically intermittent administration of PTH[1-34] promotes tendon-bone healing at an early stage via up-regulated PTH1R. This method may enable a new strategy for the promotion of tendon-bone healing after ACL reconstruction. PMID:25268612
Bi, Fanggang; Shi, Zhongli; Jiang, Shuai; Guo, Peng; Yan, Shigui
Parathyroid hormone-related protein (PTHrP) production sites in elasmobranchs
Abstract This study describes the distribution of parathyroid hormone-related protein (PTHrP) antigen and its mRNA in seven species of cartilaginous fish from six elasmobranch families. Antigen was detected using antibodies to synthetic human PTHrP and the mRNA with a riboprobe to human PTHrP gene sequence. The distribution pattern of PTHrP in the cartilaginous fish studied, reflected that observed in mammals but PTHrP further occurs in some sites unique to cartilaginous fish. Of particular note was the demonstration of PTHrP in the shark skeleton, which although considered not to contain bone, may form by a process similar to that forming the early stages of mammalian endochondral bone. The distribution of PTHrP in the elasmobranch skeleton resembled the distribution of PTHrP in the developing mammalian skeleton. Differences in the staining pattern between antisera to N-terminal PTHrP and mid-molecule PTHrP in the brain and pituitary suggested that the PTHrP molecule might be post-translationally processed in these tissues. The successful use of antibodies and a probe to human PTHrP in tissues from the early vertebrates examined in this study suggests that the PTHrP molecule is conserved from elasmobranchs to humans. PMID:12171475
Trivett, M K; Walker, T I; Macmillan, D L; Clement, J G; Martin, T J; Danks, J A
Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 is thought to be an early biomarker of disordered phosphorus metabolism in the initial stages of chronic kidney disease (CKD). We measured FGF23 in baseline samples from 3879 patients in the Chronic Renal Insufficiency Cohort study, which is a diverse cohort of patients with CKD stage 2-4. Mean serum phosphate and median parathyroid hormone (PTH) levels were in the normal range, but median FGF23 was markedly greater than in healthy populations, and increased significantly with decreasing estimated glomerular filtration rate (eGFR). High levels of FGF23, defined as being above 100 RU/ml, were more common than secondary hyperparathyroidism and hyperphosphatemia in all strata of eGFR. The threshold of eGFR at which the slope of FGF23 increased was significantly higher than the corresponding threshold for PTH based on non-overlapping 95% confidence intervals. Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increased phosphate or PTH. Hence, FGF23 measurements may be a sensitive early biomarker of disordered phosphorus metabolism in patients with CKD and normal serum phosphate levels. PMID:21389978
Isakova, Tamara; Wahl, Patricia; Vargas, Gabriela S; Guti�rrez, Orlando M; Scialla, Julia; Xie, Huiliang; Appleby, Dina; Nessel, Lisa; Bellovich, Keith; Chen, Jing; Hamm, Lee; Gadegbeku, Crystal; Horwitz, Edward; Townsend, Raymond R; Anderson, Cheryl A M; Lash, James P; Hsu, Chi-Yuan; Leonard, Mary B; Wolf, Myles
Cellular subpopulations in the bone marrow play distinct and unexplored functions in skeletal homeostasis. This study delineated a unique role of osteal macrophages in bone and parathyroid hormone (PTH)-dependent bone anabolism using murine models of targeted myeloid-lineage cell ablation. Depletion of c-fms+ myeloid lineage cells [via administration of AP20187 in the macrophage Fas-induced apoptosis (MAFIA) mouse model] reduced cortical and trabecular bone mass and attenuated PTH-induced trabecular bone anabolism, supporting the positive function of macrophages in bone homeostasis. Interestingly, using a clodronate liposome model with targeted depletion of mature phagocytic macrophages an opposite effect was found with increased trabecular bone mass and increased PTH-induced anabolism. Apoptotic cells were more numerous in MAFIA versus clodronate-treated mice and flow cytometric analyses of myeloid lineage cells in the bone marrow showed that MAFIA mice had reduced CD68+ cells, whereas clodronate liposome-treated mice had increased CD68+ and CD163+ cells. Clodronate liposomes increased efferocytosis (clearance of apoptotic cells) and gene expression associated with alternatively activated M2 macrophages as well as expression of genes associated with bone formation including Wnt3a, Wnt10b, and Tgfb1. Taken together, depletion of early lineage macrophages resulted in osteopenia with blunted effects of PTH anabolic actions, whereas depletion of differentiated macrophages promoted apoptotic cell clearance and transformed the bone marrow to an osteogenic environment with enhanced PTH anabolism. These data highlight a unique function for osteal macrophages in skeletal homeostasis. PMID:24406853
Cho, Sun Wook; Soki, Fabiana N.; Koh, Amy J.; Eber, Matthew R.; Entezami, Payam; Park, Serk In; van Rooijen, Nico; McCauley, Laurie K.
Cellular subpopulations in the bone marrow play distinct and unexplored functions in skeletal homeostasis. This study delineated a unique role of osteal macrophages in bone and parathyroid hormone (PTH)-dependent bone anabolism using murine models of targeted myeloid-lineage cell ablation. Depletion of c-fms(+) myeloid lineage cells [via administration of AP20187 in the macrophage Fas-induced apoptosis (MAFIA) mouse model] reduced cortical and trabecular bone mass and attenuated PTH-induced trabecular bone anabolism, supporting the positive function of macrophages in bone homeostasis. Interestingly, using a clodronate liposome model with targeted depletion of mature phagocytic macrophages an opposite effect was found with increased trabecular bone mass and increased PTH-induced anabolism. Apoptotic cells were more numerous in MAFIA versus clodronate-treated mice and flow cytometric analyses of myeloid lineage cells in the bone marrow showed that MAFIA mice had reduced CD68(+) cells, whereas clodronate liposome-treated mice had increased CD68(+) and CD163(+) cells. Clodronate liposomes increased efferocytosis (clearance of apoptotic cells) and gene expression associated with alternatively activated M2 macrophages as well as expression of genes associated with bone formation including Wnt3a, Wnt10b, and Tgfb1. Taken together, depletion of early lineage macrophages resulted in osteopenia with blunted effects of PTH anabolic actions, whereas depletion of differentiated macrophages promoted apoptotic cell clearance and transformed the bone marrow to an osteogenic environment with enhanced PTH anabolism. These data highlight a unique function for osteal macrophages in skeletal homeostasis. PMID:24406853
Cho, Sun Wook; Soki, Fabiana N; Koh, Amy J; Eber, Matthew R; Entezami, Payam; Park, Serk In; van Rooijen, Nico; McCauley, Laurie K
Carbonic anhydrase activity of chick osteoclasts is increased by parathyroid hormone
Embryonic chick osteoclasts were harvested, cultured for 18 h, and separated from erythrocytes, and carbonic anhydrase (CA) activity was assayed. Cultures contained 75-85% osteoclasts by acid phosphatase stain. CA activity was also determined after exposure to parathyroid hormone (PTH). Two methods of measurement were used: a {Delta}pH method, which detects the generation of hydrogen ion by carbonic anhydrase, and a mass spectrometric method, which follows the disappearance of {sup 18}O-enriched CO{sub 2}. Unstimulated osteoclasts showed CA activity that was one-third that of erythrocytes but was comparable with macrophges and chondrocytes. Osteoclasts exposed to PTH showed a twofold increase in activity, which occurred after 30 min. Ethoxzolamide (10{sup {minus}8} M) inhibited enzyme activity by 90%. Treatment of osteoclasts with calcitonin did not prevent the PTH-associated increase in CA activity. The doubling of CA activity with PTH stimulation supports the hypothesis that osteoclastic CA is intimately involved in bone resorption.
Silverton, S.F.; Dodgson, S.J.; Fallon, M.D.; Forster, R.E. II (Univ. of Pennsylvania School of Medicine, Philadelphia (USA))
Impact of parathyroid hormone on bone marrow-derived stem cell mobilization and migration
Parathyroid hormone (PTH) is well-known as the principal regulator of calcium homeostasis in the human body and controls bone metabolism via actions on the survival and activation of osteoblasts. The intermittent administration of PTH has been shown to stimulate bone production in mice and men and therefore PTH administration has been recently approved for the treatment of osteoporosis. Besides to its physiological role in bone remodelling PTH has been demonstrated to influence and expand the bone marrow stem cell niche where hematopoietic stem cells, capable of both self-renewal and differentiation, reside. Moreover, intermittent PTH treatment is capable to induce mobilization of progenitor cells from the bone marrow into the bloodstream. This novel function of PTH on modulating the activity of the stem cell niche in the bone marrow as well as on mobilization and regeneration of bone marrow-derived stem cells offers new therapeutic options in bone marrow and stem cell transplantation as well as in the field of ischemic disorders.
Huber, Bruno C; Grabmaier, Ulrich; Brunner, Stefan
Parathyroid hormone (PTH) 1-34 is known to enhance fracture healing. Tendon repair is analogous to bone healing in its dependence on the proliferation and differentiation of mesenchymal stem cells, matrix formation, and tissue remodeling.(1,2,3) We hypothesized that PTH 1-34 enhances tendon healing in a flexor digitorum longus (FDL) tendon repair model. C57Bl/6J mice were treated with either intraperitoneal PTH 1-34 or vehicle-control (PBS). Tendons were harvested at 3-28 days for histology, gene expression, and biomechanical testing. The metatarsophalangeal joint range of motion was reduced 1.5-2-fold in PTH 1-34 mice compared to control mice. The gliding coefficient, a measure of adhesion formation, was 2-3.5-fold higher in PTH 1-34 mice. At 14 days post-repair, the tensile strength was twofold higher in PTH 1-34 specimens, but at 28 days there were no differences. PTH 1-34 mice had increased fibrous tissue deposition that correlated with elevated expression of collagens and fibronectin as seen on quantitative PCR. PTH 1-34 accelerated the deposition of reparative tissue but increased adhesion formation. � 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:17-24, 2015. PMID:25266795
Lee, Daniel J; Southgate, Richard D; Farhat, Youssef M; Loiselle, Alayna E; Hammert, Warren C; Awad, Hani A; O'Keefe, Regis J
Distinctive Tooth-Extraction Socket Healing: Bisphosphonate Versus Parathyroid Hormone Therapy
Background Patients with osteoporosis who receive tooth extractions are typically on either oral bisphosphonate or parathyroid hormone (PTH) therapy. Currently, the consequence of these therapies on hard- and soft-tissue healing in the oral cavity is not clearly defined. The aim of this study is to determine the differences in the therapeutic effect on tooth-extraction wound healing between bisphosphonate and PTH therapies. Methods Maxillary second molars were extracted in Sprague Dawley rats (n = 30), and either bisphosphonate (zoledronate [Zol]), PTH, or saline (vehicle control [VC]) was administered for 10 days (n = 10 per group). Hard-tissue healing was evaluated by microcomputed tomography and histomorphometric analyses. Collagen, blood vessels, inflammatory cell infiltration, and cathepsin K expression were assessed in soft tissue using immunohistochemistry, quantitative polymerase chain reaction, and immunoblotting. Results Both therapies significantly increased bone fill and suppressed vertical bone loss. However, considerably more devital bone was observed in the sockets of rats on Zol versus VC. Although Zol increased the numbers of blood vessels, the total blood vessel area in soft tissue was significantly smaller than in VC. PTH therapy increased osteoblastic bone formation and suppressed osteoclasts. PTH therapy promoted soft-tissue maturation by suppressing inflammation and stimulating collagen deposition. Conclusion Zoledronate therapy deters whereas PTH therapy promotes hard- and soft-tissue healing in the oral cavity, and both therapies prevent vertical bone loss. PMID:23688101
Kuroshima, Shinichiro; Mecano, Rodan B.; Tanoue, Ryuichiro; Koi, Kiyono; Yamashita, Junro
T Lymphocytes Amplify the Anabolic Activity of Parathyroid Hormone Through Wnt10b Signaling
Summary Intermittent administration of parathyroid hormone (iPTH) is used to treat osteoporosis as it improves bone architecture and strength, but the underlying cellular and molecular mechanisms are unclear. Here we show that iPTH increases the production of Wnt10b by bone marrow CD8+ T cells, and induces these lymphocytes to activate canonical Wnt-signaling in pre-osteoblasts. Accordingly, in responses to iPTH, T cell null mice display diminished Wnt signaling in pre-osteoblasts and blunted osteoblastic commitment, proliferation, differentiation and lifespan which result in decreased trabecular bone anabolism and no increase in strength. Demonstrating the specific role of lymphocytic Wnt10b, iPTH has no anabolic activity in mice lacking T cell produced Wnt10b. Therefore, T cell mediated activation of Wnt signaling in osteoblastic cells plays a key permissive role in the mechanism by which iPTH increases bone strength, suggesting that T cell osteoblast cross-talk pathways may provide pharmacological targets for bone anabolism. PMID:19723499
Terauchi, Masakazu; Li, Jau-Yi; Bedi, Brahmchetna; Baek, Ki-Hyun; Tawfeek, Hesham; Galley, Sarah; Gilbert, Linda; Nanes, Mark S.; Zayzafoon, Majd; Guldberg, Robert; Lamar, David L.; Singer, Meredith A.; Lane, Timothy F.; Kronenberg, Henry M.; Weitzmann, M. Neale; Pacifici, Roberto
Parathyroid hormone (PTH) is a potent anabolic agent for the treatment of osteoporosis. However, its mechanism of action in osteoblast and bone is not well understood. In this study, we show that the anabolic actions of PTH in bone are severely impaired in both growing and adult ovariectomized mice lacking bone-related activating transcription factor 4 (ATF4). Our study demonstrates that ATF4 deficiency suppresses PTH-stimulated osteoblast proliferation and survival and abolishes PTH-induced osteoblast differentiation, which, together, compromise the anabolic response. We further demonstrate that the PTH-dependent increase in osteoblast differentiation is correlated with ATF4-dependent up-regulation of Osterix. This regulation involves interactions of ATF4 with a specific enhancer sequence in the Osterix promoter. Furthermore, actions of PTH on Osterix require this same element and are associated with increased binding of ATF4 to chromatin. Taken together these experiments establish a fundamental role for ATF4 in the anabolic actions of PTH on the skeleton. PMID:19851510
Yu, Shibing; Franceschi, Renny T.; Luo, Min; Fan, Jie; Jiang, Di; Cao, Huiling; Kwon, Tae-Geon; Lai, Yumei; Zhang, Jian; Patrene, Kenneth; Hankenson, Kurt; Roodman, G. David; Xiao, Guozhi
NASA Technical Reports Server (NTRS)
To determine whether the acute inhibition of bone formation and deficit in bone mineral induced by skeletal unloading can be prevented, we studied the effects of intermittent parathyroid hormone (PTH) administration (8 micrograms/100 g/day) on growing rats submitted to 8 days of skeletal unloading. Loss of weight bearing decreased periosteal bone formation by 34 and 51% at the tibiofibular junction and tibial midshaft, respectively, and reduced the normal gain in tibial mass by 35%. Treatment with PTH of normally loaded and unloaded animals increased mRNA for osteocalcin (+58 and +148%, respectively), cancellous bone volume in the proximal tibia (+41 and +42%, respectively), and bone formation at the tibiofibular junction (+27 and +27%, respectively). Formation was also stimulated at the midshaft in unloaded (+47%, p < 0.05), but not loaded animals (-3%, NS). Although cancellous bone volume was preserved in PTH-treated, unloaded animals, PTH did not restore periosteal bone formation to normal nor prevent the deficit in overall tibial mass induced by unloading. We conclude that the effects of PTH on bone formation are region specific and load dependent. PTH can prevent the decrease in cancellous bone volume and reduce the decrement in cortical bone formation induced by loss of weight bearing.
Halloran, B. P.; Bikle, D. D.; Harris, J.; Tanner, S.; Curren, T.; Morey-Holton, E.
Parathyroid hormone modulates the response of osteoblast-like cells to mechanical stimulation
NASA Technical Reports Server (NTRS)
Mechanical loading stimulates many responses in bone and osteoblasts associated with osteogenesis. Since loading and parathyroid hormone (PTH) activate similar signaling pathways in osteoblasts, we postulate that PTH can potentiate the effects of mechanical stimulation. Using an in vitro four-point bending device, we found that expression of COX-2, the inducible isoform of cyclooxygenase, was dependent on fluid forces generated across the culture plate, but not physiologic levels of strain in MC3T3-E1 osteoblast-like cells. Addition of 50 nM PTH during loading increased COX-2 expression at both subthreshold and threshold levels of fluid forces compared with either stimuli alone. We also demonstrated that application of fluid shear to MC3T3-E1 cells induced a rapid increase in [Ca(2+)](i). Although PTH did not significantly change [Ca(2+)](i) levels, flow and PTH did produce a significantly greater [Ca(2+)](i) response and increased the number of responding cells than is found in fluid shear alone. The [Ca(2+)](i) response to these stimuli was significantly decreased when the mechanosensitive channel inhibitor, gadolinium, was present. These studies indicate that PTH increases the cellular responses of osteoblasts to mechanical loading. Furthermore, this response may be mediated by alterations in [Ca(2+)](i) by modulating the mechanosensitive channel.
Ryder, K. D.; Duncan, R. L.
Intermittently Administered Parathyroid Hormone [1�34] Promotes Tendon-Bone Healing in a Rat Model
The objective of this study was to investigate whether intermittent administration of parathyroid hormone [1�34] (PTH[1�34]) promotes tendon-bone healing after anterior cruciate ligament (ACL) reconstruction in vivo. A rat model of ACL reconstruction with autograft was established at the left hind leg. Every day, injections of 60 ?g PTH[1�34]/kg subcutaneously were given to the PTH group rats (n = 10) for four weeks, and the controls (n = 10) received saline. The tendon-bone healing process was evaluated by micro-CT, biomechanical test, histological and immunohistochemical analyses. The effects of PTH[1�34] on serum chemistry, bone microarchitecture and expression of the PTH receptor (PTH1R) and osteocalcin were determined. Administration of PTH[1�34] significantly increased serum levels of calcium, alkaline phosphatase (AP), osteocalcin and tartrate-resistant acid phosphatase (TRAP). The expression of PTH1R on both osteocytes and chondrocyte-like cells at the tendon-bone interface was increased in the PTH group. PTH[1�34] also enhanced the thickness and microarchitecture of trabecular bone according to the micro-CT analysis. The results imply that systematically intermittent administration of PTH[1�34] promotes tendon-bone healing at an early stage via up-regulated PTH1R. This method may enable a new strategy for the promotion of tendon-bone healing after ACL reconstruction. PMID:25268612
Bi, Fanggang; Shi, Zhongli; Jiang, Shuai; Guo, Peng; Yan, Shigui
Association between Parathyroid Hormone Levels and Inflammatory Markers among US Adults
Background and Aims. High levels of parathyroid hormone (PTH) appear to be associated with an increased mortality. Previous studies concerning the relationship of inflammatory markers with hyperparathyroidism have yielded inconsistent results. This study investigated whether serum PTH concentrations were independently associated with several inflammatory markers among the US adults. Materials and Methods. Using data from the National Health and Nutrition Examination Survey, we examined the relation between serum PTH and C-reactive protein (CRP), red cell distribution width (RDW), and platelet-to-lymphocyte ratio (PLR) levels with weighted linear regression. Additionally, we examined the relation with increased modified Glasgow Prognostic Score (mGPS) by using weighted logistic regression. Results. CRP, RDW, and PLR values increased with increasing serum PTH concentration. After extensively adjusting for covariates, CRP and RDW increased linearly and across PTH categories (all P < 0.001), while PLR marginally increased (P = 0.190 and P = 0.095 using PTH as a categorical and continuous variable, resp.). The odds ratio of increased mGPS was 1.11 and 1.31 across PTH categories and with increasing PTH levels continuously. Conclusion. These nationally representative data indicate that serum PTH levels are independently associated with several inflammatory markers in the US population. The casual relationship between PTH levels and inflammation remains to be elucidated. PMID:24782595
Cheng, Shih-Ping; Liu, Chien-Liang; Liu, Tsang-Pai; Hsu, Yi-Chiung; Lee, Jie-Jen
Abstract Hypoparathyroidism is a hormone deficiency syndrome that leads to low blood calcium levels and for which current replacement therapy is inadequate. Gene transfer to salivary glands leads to safe and abundant secretion of therapeutic protein into either saliva or the bloodstream. We previously reported the successful transduction of rat submandibular glands with an adenoviral vector encoding human parathyroid hormone (Ad.hPTH), but unfortunately most of the hPTH was secreted into saliva. Because submandibular and parotid glands are morphologically and functionally different, we hypothesized that hPTH sorting might be different in parotid glands. After 2 days, the pattern of hPTH secretion from transduced parotid glands of intact rats was reversed from that of transduced submandibular glands, that is, most transgenic hPTH was detected in serum (5?�?1010 viral particles per gland; the saliva-to-serum ratio of total hPTH secreted was 0.04). Vector copies were localized to the targeted parotid glands, with none detected in liver or spleen. Ad.hPTH next was administered to parotid glands of parathyroidectomized rats. Two days after delivery no hPTH was detectable in saliva, but high levels were found in serum, leading to normalization of serum calcium and a significant increase in the urinary phosphorus-to-creatinine ratio. This study demonstrates for the first time differential sorting of transgenic hPTH between submandibular and parotid glands, suggesting that hPTH may be a valuable model protein for understanding the molecular basis of transgenic secretory protein sorting in these exocrine glands. We also show the clinical potential of salivary gland hPTH gene therapy for patients with hypoparathyroidism. PMID:20977345
Adriaansen, J.; Perez, P.; Zheng, C.; Collins, M.T.
Extracellular Ca(++) stimulates membrane-bound calcium-sensing receptors (CaRs). CaRs stimulation leads to PGE2-mediated decrease in protein content of Na(+)-K(+)-2Cl(-) co-transporters (BSC-1) in the thick ascending limb (TAL) of Henle's loop and of aquaporin 2 (AQP2) water channels in collecting ducts. Parathyroid hormone (PTH) increases CaRs and decreases BSC-1 and AQP2 tubular content. To assess the Ca(++)-dependent diuretic system in preascitic cirrhosis, we evaluated renal function, hormonal status, PGE2 urinary excretion, and renal content of BSC-1 and CaRs in three groups of rats: control rats received s.c. 5% glucose solution; two groups of rats with CCl4-induced preascitic cirrhosis received either s.c. glucose solution or five s.c. doses of 10 mcg/Kg PTH (one dose every 12 hours) prior to study. Cirrhotic rats, when compared to controls, showed reduced urine volume and sodium excretion; moreover, western blot analysis revealed reduced CaRs and increased BSC-1 protein content in cirrhotic rat kidneys. S.c. administration of PTH normalized urine and sodium excretion in cirrhotic rats and also increased renal plasma flow, PGE2 urinary excretion, and free-water clearance. Finally, PTH reduced BSC-1 and augmented CaRs content in cirrhotic rat kidneys. In conclusion, in preascitic cirrhosis sodium retention is associated with down-regulation of renal CaRs and up-regulation of tubular Na(+)-K(+)-2Cl(-) co-transporters. PTH returns these biomolecular changes, along with sodium and urine excretions, to normality, suggesting that exaggerated sodium reabsorption occurs primarily in the Henle's loop in preascitic cirrhosis. PMID:25371524
Sansoe, G; Mastrocola, R; Aragno, M; Parola, M
Introduction. Primary hyperparathyroidism (PHP) is characteristically determined by high levels of calcium and high or inappropriate levels of parathyroid hormone (PTH). Technological advances have dramatically changed the surgical technique over the years once intraoperative parathyroid hormone (IOPTH) assay had allowed for focused approaches. Objective. To evaluate our 10-year experience in employing a rapid intraoperative PTH assay for PHP. Methods. A prospective cohort of 91 PHP-operated patients in a tertiary institution in S�o Paulo, Brazil, from June 2000 to April 2011. Results. We had 85 (93.4%) successful parathyroidectomies, 6 (6.6%) failed parathyroidectomies in 91 previous unexplored patients, and 5 (100%) successful remedial surgeries. The IOPTH was true-positive in 88.5%, true-negative in 7.3%, false-positive in 2.1%, and false-negative in 2.1% of the procedures. IOPTH was able to obviate additional exploration or to ask for additional exploration in 92 (95.8%) procedures. Conclusion. The IOPTH revealed to be an important technological adjunct in the current parathyroid surgery for PHP. PMID:22523718
Neves, M. C.; Ohe, M. N.; Rosano, M.; Abrahao, M.; Cervantes, O.; Lazaretti-Castro, M.; Vieira, J. G. H.; Kunii, I. S.; Santos, R. O.
Background��Intraoperative parathyroid hormone (IoPTH) testing is useful in the management of hyperparathyroidism. The successful removal\\u000a of hypersecreting parathyroids is indicated by a decrease in PTH levels >50% within 15�min. A subset of patients with mild\\u000a hyperparathyroidism will actually have starting PTH levels in the normal range. We sought to determine if IoPTH testing is\\u000a necessary in these patients and if
Amal AlhefdhiScott; Scott N. Pinchot; Ruth Davis; Rebecca S. Sippel; Herbert Chen
Parathyroid hormone-dependent signaling pathways regulating genes in bone cells
NASA Technical Reports Server (NTRS)
Parathyroid hormone (PTH) is an 84-amino-acid polypeptide hormone functioning as a major mediator of bone remodeling and as an essential regulator of calcium homeostasis. PTH and PTH-related protein (PTHrP) indirectly activate osteoclasts resulting in increased bone resorption. During this process, PTH changes the phenotype of the osteoblast from a cell involved in bone formation to one directing bone resorption. In addition to these catabolic effects, PTH has been demonstrated to be an anabolic factor in skeletal tissue and in vitro. As a result, PTH has potential medical application to the treatment of osteoporosis, since intermittent administration of PTH stimulates bone formation. Activation of osteoblasts by PTH results in expression of genes important for the degradation of the extracellular matrix, production of growth factors, and stimulation and recruitment of osteoclasts. The ability of PTH to drive changes in gene expression is dependent upon activation of transcription factors such as the activator protein-1 family, RUNX2, and cAMP response element binding protein (CREB). Much of the regulation of these processes by PTH is protein kinase A (PKA)-dependent. However, while PKA is linked to many of the changes in gene expression directed by PTH, PKA activation has been shown to inhibit mitogen-activated protein kinase (MAPK) and proliferation of osteoblasts. It is now known that stimulation of MAPK and proliferation by PTH at low concentrations is protein kinase C (PKC)-dependent in both osteoblastic and kidney cells. Furthermore, PTH has been demonstrated to regulate components of the cell cycle. However, whether this regulation requires PKC and/or extracellular signal-regulated kinases or whether PTH is able to stimulate other components of the cell cycle is unknown. It is possible that stimulation of this signaling pathway by PTH mediates a unique pattern of gene expression resulting in proliferation in osteoblastic and kidney cells; however, specific examples of this are still unknown. This review will focus on what is known about PTH-mediated cell signaling, and discuss the established or putative PTH-regulated pattern of gene expression in osteoblastic cells following treatment with catabolic (high) or anabolic (low) concentrations of the hormone.
Swarthout, John T.; D'Alonzo, Richard C.; Selvamurugan, Nagarajan; Partridge, Nicola C.
The importance of fibroblast growth factor (FGF)-23 as part of a hormonal bone-kidney-axis has been well established. Lately, FGF-23 has been suggested as an independent risk factor of death in patients on chronic hemodialysis. Hyperparathyroidism is a common feature of advanced kidney failure or end-stage renal disease. The independent effect of elevated parathyroid hormone (PTH) levels on FGF-23 secretion is still a matter of debate and has not yet been studied in an in vitro model of human bone marrow cells (BMC) during osteogenic differentiation. BMC from three different donors were cultivated for 4 weeks in cell cultures devoid of vitamin D either without 1-34 PTH or with PTH concentrations of 10 or 100 pmol/L, respectively. After 28 days, protein expression of the cells was determined by immunocytochemical staining, whereas real time-polymerase chain reaction served to analyze gene expression of several osteoblastic (osteocalcin, RANKL, Runx-2 and ostase) and osteoclastic markers (RANK, TRAP-5b). The concentrations of FGF-23, ostase and TRAP-5b were determined by ELISA at weeks 2, 3 and 4. We found a basal expression of FGF-23 with no increase in FGF-23 secretion after stimulation with 10 pmol/L 1-34 PTH. Stimulation with 100 pmol/L PTH resulted in an increase in FGF-23 expression (14.1�3.6 pg/mL with no PTH, 13.7�4.0 pg/mL with 10 pmol/L, P=0.84 and 17.6�3.4 pg/mL with 100 pmol/L, P=0.047). These results suggest a vitamin D and PTH-independent FGF-23 expression in human BMC after osteogenic stimulation. As only higher PTH levels stimulated FGF-23 expression, a threshold level might be hypothesized. PMID:25002935
Tillmann, Frank-Peter; Hofen, Daniela; Herten, Monika; Krauspe, Rudiger; Jager, Marcus
Parathyroid hormone (PTH)-stimulated signal transduction through mechanisms alternate to adenosine 3{prime},5{prime}-cyclic monophosphate (cAMP) production were studied in UMR 106-01 cells, a cell line with an osteoblastic phenotype. PTH produced transient, dose-related increases in cytosolic calcium ((Ca{sup 2+}){sub i}), inositol trisphosphates, and diacylglycerol (DAG). Both inositol 1,4,5-trisphosphate (Ins-1,4,5P{sub 3}) and inositol 1,3,4-trisphosphate (Ins-1,3,4P{sub 3}) production were rapidly stimulated by PTH. Consistent with the production of Ins-1,3,4P{sub 3}, rapid stimulation of late eluting inositol tetrakisphosphate was observed. The effects on the inositol phosphates were induced rapidly, consistent with roles as signals for changes in (Ca{sup 2+}){sub i}. In saponin-permeabilized UMR 106-01 cells, Ins-1,4,5P{sub 3} stimulated {sup 45}Ca release from a nonmitochondrial intracellular pool. Thus the hypothesis that PTH-stimulated Ins-1,4,5P{sub 3} production initiates Ca{sup 2+} release and contributes to transient elevations of (Ca{sup 2+}){sub i} is supported. These data suggest that stimulation of cAMP production during PTH stimulation may negatively affect production of rises in (Ca{sup 2+}){sub i} during PTH stimulation. The inactivation of the inhibitory G protein of adenylate cyclase by pertussis toxin could explain its action similar to cAMP analogues. Cyclci nucleotides diminish the effects of PTH on (Ca{sup 2+}){sub i}, probably interacting on a biochemical step subsequent to or independent of Ins-1,4,5P{sub 3} release.
Civitelli, R.; Reid, I.R.; Westbrook, S.; Avioli, L.V.; Hruska, K.A. (Jewish Hospital of St. Louis, MO (USA))
Renal phosphate reabsorption across the brush border membrane (BBM) in the proximal tubule is mediated by at least three transporters, NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3), and Pit-2 (SLC20A2). Parathyroid hormone (PTH) is a potent phosphaturic factor exerting an acute and chronic reduction in proximal tubule phosphate reabsorption. PTH acutely induces NaPi-IIa internalization from the BBM and lysosomal degradation, but its effects on NaPi-IIc and Pit-2 are unknown. In rats adapted to low phosphate diet, acute (30 and 60 min) application of PTH decreased BBM phosphate transport rates both in the absence and the presence of phosphonoformic acid, an inhibitor of SLC34 but not SLC20 transporters. Immunohistochemistry showed NaPi-IIa expression in the S1 to the S3 segment of superficial and juxtamedullary nephrons; NaPi-IIc was only detectable in S1 segments and Pit-2 in S1 and weakly in S2 segments of superficial and juxtamedullary nephrons. PTH reduced NaPi-IIa staining in the BBM with increased intracellular and lysosomal appearance. NaPi-IIa internalization was most prominent in S1 segments of superficial nephrons. We did not detect changes in NaPi-IIc and Pit-2 staining over this time period. Blockade of lysosomal protein degradation with leupeptin revealed NaPi-IIa accumulation in lysosomes, but no lysosomal staining for NaPi-IIc or Pit-2 could be detected. Immunoblotting of BBM confirmed the reduction in NaPi-IIa abundance and the absence of any effect on NaPi-IIc expression. Pit-2 protein abundance was also significantly reduced by PTH. Thus, function and expression of BBM phosphate cotransporters are differentially regulated allowing for fine-tuning of renal phosphate reabsorption. PMID:20526720
Picard, Nicolas; Capuano, Paola; Stange, Gerti; Mihailova, Marija; Kaissling, Brigitte; Murer, Heini; Biber, J�rg; Wagner, Carsten A
Parathyroid Hormone Related-Protein Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer
Parathyroid hormone-related protein (PTHrP) possesses a variety of physiological and developmental functions and is also known to facilitate the progression of many common cancers, notably their skeletal invasion, primarily by increasing bone resorption. The purpose of this study was to determine whether PTHrP could promote epithelial-to-mesenchymal transition (EMT), a process implicated in cancer stem cells that is critically involved in cancer invasion and metastasis. EMT was observed in DU 145 prostate cancer cells stably overexpressing either the 1-141 or 1-173 isoform of PTHrP, where there was upregulation of Snail and vimentin and downregulation of E-cadherin relative to parental DU 145. By contrast, the opposite effect was observed in PC-3 prostate cancer cells where high levels of PTHrP were knocked-down via lentiviral siRNA transduction. Increased tumor progression was observed in PTHrP-overexpressing DU 145 cells while decreased progression was observed in PTHrP-knockdown PC-3 cells. PTHrP-overexpressing DU 145 formed larger tumors when implanted orthoptopically into nude mice and in one case resulted in spinal metastasis, an effect not observed among mice injected with parental DU 145 cells. PTHrP-overexpressing DU 145 cells also caused significant bone destruction when injected into the tibiae of nude mice, while parental DU 145 cells caused little to no destruction of bone. Together, these results suggest that PTHrP may work through EMT to promote an aggressive and metastatic phenotype in prostate cancer, a pathway of importance in cancer stem cells. Thus, continued efforts to elucidate the pathways involved in PTHrP-induced EMT as well as to develop ways to specifically target PTHrP signaling may lead to more effective therapies for prostate cancer. PMID:24465715
Rahimy, Elham; Yang, Meng; Hoffman, Robert M.; Wang-Rodriguez, Jessica; Deftos, Leonard J.
'Biased agonism' refers to the ability of a ligand to selectively recruit different intracellular signaling proteins to elicit distinct phenotypic effects in cells. While conventional G protein-coupled receptor (GPCR) agonism and antagonism can be regarded as modulating the quantity of efficacy, functionally selective or 'biased' ligands qualitatively change the trafficking of information flowing across the plasma membrane. The concept of ligand directed signaling fundamentally raises the potential of pharmacologic agents with novel therapeutic profiles possessing improved therapeutic efficacy or reduced side effects. Currently, there is little experimental evidence that biased ligands offer advantages over conventional agonists/antagonists in vivo. Recent work examining biased agonism at the type I parathyroid hormone receptor (PTH1R) demonstrates that selective activation of G protein-independent arrestin-mediated signaling pathways elicits a physiologic response in bone distinct from that induced by the conventional PTH1R agonist PTH(1-34). While intermittent (daily) administration of PTH(1-34) (teriparitide) is effective in increasing bone formation, PTH(1-34) administration is also associated with increases in bone resorption and a propensity to promote hypercalcemia/hypercalcuria. In contrast, D-Trp12,Tyr34-bPTH(7-34) (PTH-?arr), an arrestin pathway-selective agonist for the PTH1R, induces anabolic bone formation independent of classic G protein-coupled signaling mechanisms. Unlike PTH(1-34), PTH-?arr appears to 'uncouple' the anabolic effects of PTH1R activation from its catabolic and calcitropic effects. Such findings offer evidence that arrestin pathway-selective GPCR agonists can elicit potentially beneficial effects in vivo that cannot be achieved using conventional agonist or antagonist ligands. PMID:22681253
Bohinc, B N; Gesty-Palmer, D
Parathyroid hormone-related protein is a gravisensor in lung and bone cell biology
NASA Astrophysics Data System (ADS)
Parathyroid Hormone-related Protein (PTHrP) has been shown to be essential for the development and homeostatic regulation of lung and bone. Since both lung and bone structure and function are affected by microgravity, we hypothesized that 0 � g down-regulates PTHrP signaling. To test this hypothesis, we suspended lung and bone cells in the simulated microgravity environment of a Rotating Wall Vessel Bioreactor, which simulates microgravity, for up to 72 hours. During the first 8 hours of exposure to simulated 0 � g, PTHrP expression fell precipitously, decreasing by 80-90%; during the subsequent 64 hours, PTHrP expression remained at this newly established level of expression. PTHrP production decreased from 12 pg/ml/hour to 1 pg/ml/hour in culture medium from microgravity-exposed cells. The cells were then recultured at unit gravity for 24hours, and PTHrP expression and production returned to normal levels. Based on these findings, we have obtained bones from rats flown in space for 2 weeks (Mission STS-58, SL-2). Analysis of PTHrP expression by femurs and tibias from these animals (n=5) revealed that PTHrP expression was 60% lower than in bones from control ground-based rats. Interestingly, there were no differences in PTHrP expression by parietal bone from space-exposed versus ground-based animals, indicating that the effect of weightlessness on PTHrP expression is due to the unweighting of weight-bearing bones. This finding is consistent with other studies of microgravity-induced osteoporosis. The loss of the PTHrP signaling mechanism may be corrected using chemical agents that up-regulate this pathway. In conclusion, PTHrP represents a stretch-sensitive paracrine signaling mechanism that may sense gravity.
Torday, J. S.
Parathyroid hormone activates the orphan nuclear receptor Nurr1 to induce FGF23 transcription.
Parathyroid hormone (PTH) increases FGF23 mRNA and protein levels in vivo and in vitro. Here we tested whether the increased FGF23 expression by PTH is mediated by the orphan nuclear receptor Nurr1. PTH increased Nurr1 mRNA levels prior to elevation of FGF23 mRNA levels in UMR-106 rat osteoblast-like cells. Activation of PKA increased both FGF23 and Nurr1 mRNA levels. Modification of Nurr1 expression showed that Nurr1 is essential for the PTH-mediated increase in FGF23 and luciferase reporter gene experiments identified a functional promoter region containing several potential Nurr1 binding sites. Chromatin immunoprecipitation assays confirmed the binding of Nurr1 to these regions in the FGF23 promoter. In vivo, Nurr1 mRNA and protein levels were increased in calvaria from rats with experimental CKD together with high PTH and FGF23 expression. Calcimimetics decrease PTH and FGF23 levels in CKD patients. Importantly, in rats with experimental CKD, the calcimimetic R568 decreased PTH expression, calvaria Nurr1 mRNA and protein levels, and FGF23 mRNA. Immunohistochemistry for Nurr1 showed an increase in the number of Nurr1 expressing osteocytes in the femurs of rats with CKD and this was decreased by R568. Thus, the effect of PTH to increase FGF23 transcription is mediated by Nurr1 in vitro and in vivo. In CKD, calcimimetics decrease PTH, which in turn decreases Nurr1 and consequently FGF23. PMID:24940803
Meir, Tomer; Durlacher, Karina; Pan, Zheng; Amir, Gail; Richards, William G; Silver, Justin; Naveh-Many, Tally
Parathyroid hormone induces the Nrna family of nuclear orphan receptors in vivo
Parathyroid hormone (PTH) has both anabolic and catabolic effects on bone metabolism, although the molecular mechanisms mediating these effects are largely unknown. Among the transcription factors induced by Pth in osteoblasts are the nerve growth factor-inducible factor B (NR4A; NGFI-B) family of orphan nuclear receptors: Nurr1, Nur77, and NOR-1. PTH induces NR4A members through the cAMP-protein kinase A (PKA) pathway in vitro. We report here that PTH rapidly and transiently induced expression of all three NR4A genes in PTH-target tissues in vivo. In calvaria, long bones, and kidneys, NR4A induction was maximal 0.5-1 h after a single intraperitoneal (i.p.) injection of 80 {mu}g/kg PTH. Nur77 demonstrated the highest expression, followed, in order, by Nurr1 and NOR-1. In calvaria and long bone, PTH-induced expression of each NR4A gene was detectable at 10 {mu}g/kg i.p. with maximum induction at 40-80 {mu}g/kg. PTH (3-34) did not induce NR4A mRNA levels in calvaria, long bone, and kidney in vivo, confirming our in vitro results that NR4A genes are induced primarily through the cAMP-PKA pathway. The magnitude of PTH-induced NR4A expression was comparable in vivo and in vitro. However, NR4A mRNA levels peaked and returned to baseline faster in vivo. Both in vivo and in vitro, PTH induced NR4A pre-mRNA levels suggesting that induction of these genes is, at least in part, through activation of mRNA synthesis. The in vivo induction of the NR4A family members by PTH suggests their involvement in, at least some, PTH-induced changes in bone metabolism.
Pirih, Flavia Q. [Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095 (United States)]. E-mail: email@example.com; Aghaloo, Tara L. [Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095 (United States)]. E-mail: firstname.lastname@example.com; Bezouglaia, Olga [Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095 (United States)]. E-mail: email@example.com; Nervina, Jeanne M. [Section of Orthodontics, UCLA School of Dentistry, Los Angeles, CA 90095 (United States)]. E-mail: firstname.lastname@example.com; Tetradis, Sotirios [Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, CA 90095 (United States); UCLA Molecular Biology Institute, Los Angeles, CA 90095 (United States); E-mail: email@example.com
Background and purpose Intermittent administration of parathyroid hormone (PTH) has an anabolic effect on bone, as confirmed in human osteoporosis studies, distraction osteogenesis, and fracture healing. PTH in rat models leads to improved fixation of implants in low-density bone or screw insertion transcortically. Material and methods We examined the effect of human PTH (1�34) on the cancellous osseointegration of unloaded implants inserted press-fit in intact bone of higher animal species. 20 dogs were randomized to treatment with human PTH (1�34), 5 ?g/kg/day subcutaneously, or placebo for 4 weeks starting on the day after insertion of a cylindrical porous coated plasma-sprayed titanium alloy implant in the proximal metaphyseal cancellous bone of tibia. Osseointegration was evaluated by histomorphometry and fixation by push-out test to failure. Results Surface fraction of woven bone at the implant interface was statistically significantly higher in the PTH group by 1.4 fold with (median (interquartile range) 15% (13�18)) in the PTH group and 11% (7�13) in control. The fraction of lamellar bone was unaltered. No significant difference in bone or fibrous tissue was observed in the circumferential regions of 0�500, 500�1,000, and 1,000�2,000 ?m around the implant. Mechanically, the implants treated with PTH showed no significant differences in total energy absorption, maximum shear stiffness, or maximum shear strength. Interpretation Intermittent treatment with PTH (1�34) improved xhistological osseointegration of a prosthesis inserted press-fit at surgery in cancellous bone, with no additional improvement of the initial mechanical fixation at this time point. PMID:22880714
Parathyroid hormone (PTH) stimulates hematopoiesis in mouse models. The involvement of osteoblasts in this process has been well investigated; however, the effects of PTH on human hematopoiesis and bone marrow mesenchymal stromal cells (BM-MSCs) are unclear. Here, we show that BM-MSCs contribute to the hematopoiesis-stimulating effects of PTH via upregulation of cadherin-11 (CDH11). When culture-expanded human BM-MSCs were stimulated with PTH, their ability to expand cocultured CD34(+) hematopoietic progenitor cells (HPCs) was enhanced. Furthermore, when PTH-treated BM-MSCs were subcutaneously implanted into NOD/SCID mice, the induction of hematopoietic cells was enhanced. Culture-expanded human BM-MSCs expressed CDH11, and the level of CDH11 expression increased following PTH stimulation. Depletion of CDH11 expression in BM-MSCs using small interfering RNA abolished the enhancement of HPC expansion by PTH-treated BM-MSCs. In lethally irradiated mice that underwent BM transplantation, CDH11 expression in BM-MSCs was higher and survival was better in PTH-treated mice than in control mice. The number of hematopoietic cells in BM and the number of red blood cells in peripheral blood were higher in PTH-treated mice than in control mice. Our results demonstrate that PTH stimulates hematopoiesis through promoting the upregulation of CDH11 expression in BM-MSCs, at least in part. PTH treatment may be an effective strategy to enhance the ability of BM-MSCs to support hematopoiesis. PMID:24648356
Yao, Hisayuki; Miura, Yasuo; Yoshioka, Satoshi; Miura, Masako; Hayashi, Yoshihiro; Tamura, Akihiro; Iwasa, Masaki; Sato, Atsushi; Hishita, Terutoshi; Higashi, Yayoi; Kaneko, Hitomi; Ashihara, Eishi; Ichinohe, Tatsuo; Hirai, Hideyo; Maekawa, Taira
Parathyroid hormone and arterial dysfunction in the Multi-Ethnic Study of Atherosclerosis
Objective High circulating concentrations of parathyroid hormone (PTH) have been associated with increased risks of hypertension, left ventricular hypertrophy, congestive heart failure, and cardiovascular mortality. Impaired arterial function is a potential mechanism for these associations. We tested whether serum PTH concentration is associated with measures of arterial function. Design Cross-sectional study. Participants 6,545 persons without clinical cardiovascular disease participating in the community-based Multi-Ethnic Study of Atherosclerosis. Measurements Brachial artery flow-mediated dilation as well as aortic pulse pressure and arterial pulse parameters derived from Windkessel modeling of the radial pressure waveform. Results Higher serum PTH concentration was associated with lower brachial artery flow-mediated dilation (mean difference ?0.09% per 10 pg/mL PTH), higher aortic pulse pressure (0.53 mmHg per 10 pg/mL), and reduced Windkessel capacitive index C1 (large artery elasticity, ?0.12 ml/mmHg X 10 per 10 pg/mL), adjusting for potential confounding variables (all p-values ? 0.001). These relationships were independent of serum calcium concentration, serum 25-hydroxyvitamin D concentration, and estimated glomerular filtration rate and were consistent across relevant participant subgroups. Associations of PTH with aortic pulse pressure and capacitive index C1 were attenuated after adjustment for blood pressure. Serum PTH concentration was not associated with the oscillatory index C2 (small artery elasticity). Conclusions Higher serum PTH concentration was associated with impaired endothelial function, increased aortic pulse pressure, and decreased capacitive index C1 in a large, diverse, community-based population. These relationships may help explain previously observed associations of elevated PTH with cardiovascular disease. PMID:23402353
Bosworth, Cortney; Sachs, Michael C.; Duprez, Daniel; Hoofnagle, Andrew N.; Ix, Joachim H.; Jacobs, David R.; Peralta, Carmen A.; Siscovick, David S.; Kestenbaum, Bryan; de Boer, Ian H.
Effect of Zoledronate on the Responses of Osteocytes to Acute Parathyroid Hormone
The bone anabolic effect of parathyroid hormone (PTH) therapy is blunted when used in patients who were previously on bisphosphonate treatment. Osteocytes may play a role in the bisphosphonate silencing effect on PTH therapy since bisphosphonates have been shown to reach the lacuno-canalicular system. In vivo osteocyte studies pose a significant challenge. For the current study, we developed a simple method to isolate RNA from the cortical bone enriched with osteocytes. Our purpose was to investigate how zoledronate (ZA) treatment modulates the responses of osteocytes and the bone marrow (BM) to an acute PTH treatment. Mice received ZA treatment for 3 months and a single PTH injection prior to euthanasia. Bone was histomorphometrically evaluated. Gene expression was assessed at the RNA level in osteocytes and BM. Endothelial progenitor cells (EPCs) and ??T-cells were analyzed in the BM and blood using flow cytometry. We found that ZA treatment altered bone responses to PTH. The expression of sfrp4, a Wnt antagonist, was significantly increased in ZA-affected osteocytes. BM EPCs were increased in response to acute PTH but not when treatment was combined with ZA. ZA treatment augmented EPCs in the BM but not in blood which suggests that ZA treatment may have differential effects between the BM and blood. These findings indicate that osteocytes and BM EPCs in mice on ZA treatment respond differently to acute PTH from those not receiving ZA. This may partially explain the mechanisms of previous reports that ZA therapy attenuates the anabolic effect of PTH in bone. PMID:23503790
Kuroshima, Shinichiro; Elliott, Kirk William; Yamashita, Junro
Effects of Age on Parathyroid Hormone Signaling in Human Marrow Stromal Cells
Summary Human bone marrow stromal cells (hMSCs) have the potential to differentiate into osteoblasts; there are age-related decreases in their proliferation and differentiation to osteoblasts. Parathyroid hormone (PTH), when applied intermittently in vivo, has osteoanabolic effects in a variety of systems. In this study, we compared PTH signaling and osteoanabolic effects in hMSCs from young and old subjects. There were age-related decreases in expression of PTH/PTHrP receptor type 1 (PTHR1) gene (p=0.049, n=19) and in PTH activation of CREB (p=0.029, n=7) and PTH stabilization of ?-catenin (p=0.018, n=7). Three human PTH peptides, PTH1�34, PTH1-31C (Ostabolin-C, Leu27, Cyclo[Glu22-Lys26]-hPTH1�31), and PTH1�84 (10 nM) stimulated osteoblast differentiation with hMSCs. Treatment with PTH1�34 resulted in a significant 67% increase in alkaline phosphatase (ALP) activity in hMSCs obtained from younger subjects (<50-year-old, n=5), compared with an 18% increase in hMSCs from elders (>55-year-old, n=7). Both knockdown of CREB and treatment with a PKA inhibitor H-89 blocked PTH stimulation of osteoblast differentiation in hMSCs from young subjects. The PTH peptides significantly stimulated proliferation of hMSCs. Treatment with PTH1�34 resulted in an average of twice as many cells in cultures of hMSCs from young subjects (n=4), but had no effect with hMSCs from elders (n=7). Upregulation of PTHR1 by 24-hour pre-treatment with 100 nM dexamethasone rescued PTH stimulation of proliferation in hMSCS from elders. In conclusion, age-related intrinsic alterations in signaling responses to osteoanabolic agents like PTH may contribute to cellular and tissue aging of the human skeleton. PMID:21518242
Zhou, Shuanhu; Bueno, Ericka M.; Kim, Sung Won; Amato, Ilaria; Shen, Longxiang; Hahne, Jochen; Bleiberg, Ilan; Morley, Paul; Glowacki, Julie
Parathyroid hormone (PTH) dose dependently inhibits growth factor- and stress-induced osteoblast proliferation via inactivating mitogen-activated protein kinase (MAPK) signaling pathways. Osteoblasts have recently been shown to express MAPK phosphatase (MKP)-1, a dual-specific phosphatase inactivator of MAPK. Investigated was the role of MKPs in the PTH-induced attenuation of MAPK and Jun N-terminal kinase (JNK) signaling in osteoblast-like UMR106-01 cells. PTH induced a persistent inhibition of p42/44 MAPK and JNK phosphorylation starting at 10 min of incubation and lasting for at least 2 h. Actinomycin D affected both p42/44 MAPK and JNK dephosphorylation by PTH, suggesting a transcription-dependent mechanism of action. PTH rapidly and transiently induced expression of MKP-1. MKP-1 mRNA was already elevated after 10 min of 10(-7) M PTH incubation, reached maximal expression after 30 to 60 min, and remained elevated after 4 h. MKP-1 protein was also upregulated within 30 to 60 min of PTH administration. The protein kinase A inhibitor H89 partly reduced PTH-induced MKP-1 expression, but the protein kinase C inhibitor bisindolylmaleimide had no effect, suggesting that PTH induces MKP-1 mainly via the protein kinase A pathway. MKP-2 mRNA was downregulated after 2 h after an early period of induction, and MKP-3 mRNA was immediately reduced. Ro 318-220 did not affect PTH-induced MAPK inactivation but effectively blocked JNK dephosphorylation. The time course of PTH-induced MKP-1 protein expression closely correlated with JNK dephosphorylation. PTH attenuates the stress-induced JNK signaling pathway in osteoblasts via induction of MKP-1 synthesis but inhibits the p42/44 MAPK pathway mainly via transcription-independent mechanisms. PMID:15504937
H�mme, Meike; Schmitt, Claus P; Mehls, Otto; Schaefer, Franz
Effects of age on parathyroid hormone signaling in human marrow stromal cells.
Human bone marrow stromal cells (hMSCs) have the potential to differentiate into osteoblasts; there are age-related decreases in their proliferation and differentiation to osteoblasts. Parathyroid hormone (PTH), when applied intermittently in vivo, has osteoanabolic effects in a variety of systems. In this study, we compared PTH signaling and osteoanabolic effects in hMSCs from young and old subjects. There were age-related decreases in expression of PTH/PTHrP receptor type 1 (PTHR1) gene (P?=?0.049, n?=?19) and in PTH activation of CREB (P?=?0.029, n?=?7) and PTH stabilization of ?-catenin (P?=?0.018, n?=?7). Three human PTH peptides, PTH1-34, PTH1-31C (Ostabolin-C, Leu(27) , Cyclo[Glu(22) -Lys(26) ]-hPTH1-31), and PTH1-84 (10?nm), stimulated osteoblast differentiation with hMSCs. Treatment with PTH1-34 resulted in a significant 67% increase in alkaline phosphatase activity in hMSCs obtained from younger subjects (<50?years old, n?=?5), compared with an 18% increase in hMSCs from elders (>55?years old, n?=?7). Both knockdown of CREB and treatment with a protein kinase A inhibitor H-89 blocked PTH stimulation of osteoblast differentiation in hMSCs from young subjects. The PTH peptides significantly stimulated proliferation of hMSCs. Treatment with PTH1-34 resulted in an average of twice as many cells in cultures of hMSCs from young subjects (n?=?4), but had no effect with hMSCs from elders (n?=?7). Upregulation of PTHR1 by 24-h pretreatment with 100?nm dexamethasone rescued PTH stimulation of proliferation in hMSCS from elders. In conclusion, age-related intrinsic alterations in signaling responses to osteoanabolic agents like PTH may contribute to cellular and tissue aging of the human skeleton. PMID:21518242
Zhou, Shuanhu; Bueno, Ericka M; Kim, Sung Won; Amato, Ilaria; Shen, Longxiang; Hahne, Jochen; Bleiberg, Ilan; Morley, Paul; Glowacki, Julie
Metabolism and Action of the Hormone Vitamin D
Extensive experimental evidence has established a significant role of calciferol in the maintenance of normal calcium homeostasis. Present knowledge indicates that vitamin D3 must first be converted to 25-OH-D3 and then to 1,25(OH)2D3, the most active known form of the steroid. Many of the factors regulating the rate of production of this last steroid from its precurser have been evaluated, and the concept that vitamin D functions as a steroid hormone seems to be well established. Deranged action of calciferol, caused by impaired metabolism of the steroid or through altered sensitivity of target tissues, may be involved in the pathophysiology of several disease states with abnormal calcium metabolism. It is noted that liver disease, osteomalacia due to anticonvulsant therapy, chronic renal failure, hypophosphatemic rickets, hypoparathyroidism, hyperparathyroidism, sarcoidosis and idiopathic hypercalciuria have possible relation to alterations in metabolism or action of vitamin D. The future clinical availability of 1,25(OH)2D3 and other analogs of this steroid may offer potential therapeutic benefit in the treatment of certain of the disease entities discussed. PMID:4365934
Coburn, Jack W.; Hartenbower, David L.; Norman, Anthony W.
Background: Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and a defect in antibody production. Herein we describe 3 patients diagnosed with CVID in whom vitamin D deficiency was detected in the absence of enteropathy. Methods: Biochemical and immunological analysis, serum osteocalcin, parathyroid hormone, 25-OH vitamin D, 1,25(OH)2 vitamin D, vitamin A, vitamin E, urinary calcium, and deoxypyridinoline measurements were
�m�r Ardeniz; Aytul Sin; G�khan �zgen; Fulya Gunsar; Nihal Mete; Okan Gulbahar; Ali Kokuludag
Effect of Vitamin D Nutrition on Parathyroid Adenoma Weight: Pathogenetic and Clinical Implications
In primary hyperparathyroidism, adenoma size is a major deter- minant of disease severity and manner of presentation, but the reason for the large variation in size (.100-fold) is unknown. One factor could be the level of vitamin D nutrition, because in India, where vitamin D deficiency is endemic, adenomas are larger and the disease more severe than in the U.S.
Assessment of recombinant human parathyroid hormone: correlation of LC methods with bioassays.
Reversed-phase liquid chromatography (RP-LC) and size exclusion liquid chromatography (SE-LC) methods were validated for the assessment of recombinant human parathyroid hormone (rhPTH 1-34). The gradient RP-LC method was carried out on a Zorbax 300 SB C(18) column (150 mm � 4.6 mm i.d.), maintained at 40 �C. The mobile phase A consisted of 0.1 M sodium sulphate buffer, pH 2.3, and the mobile phase B was acetonitrile. The SE-LC method was carried out on a BioSep-SEC-S 2000 column (300 mm � 7.8 mm i.d.), maintained at 25 �C. The mobile phase consisted of 0.1 M phosphoric acid buffer, pH 2.5, run isocratically at a flow rate of 0.7 mL min(-1). Chromatographic separation was obtained with retention times of 12.2 min, and 13.2 min, and was linear over the concentration range of 1-250 ?g mL(-1) (r(2) = 0.9997) and 2-300 ?g mL(-1) (r(2) = 0.9993), respectively, for RP-LC and SE-LC, with photodiode array (PDA) detection at 214 nm. Specificity was established in degradation studies, which also showed that there was no interference of the excipients. Equally, the accuracy was 100.49% and 100.22%, with bias lower than 1.12% and 0.81% respectively. Moreover, the in vitro cytotoxicity test of related proteins and higher molecular weight forms showed significant differences (p < 0.05). Chromatographic methods were applied for the content/potency assessment of rhPTH and related proteins in biopharmaceutical injectable dosage forms, and the results were correlated with those of in vitro and in vivo bioassays. It is concluded that the employment of the methods in conjunction allows a great improvement in monitoring stability, contributing to evaluate alternatives which improve the quality control and thereby assure the therapeutic efficacy of the biotechnology-derived medicine. PMID:23324983
Stamm, Fernanda P; Calegari, Guilherme Z; de Freitas, Guilherme W; Souto, Ricardo B; Porto, Larissa P; Cardoso, Cl�vis D A; Dalmora, S�rgio L
Background: The first description of the use of a rapid assay for the measurement of intact parathyroid hor- mone (PTH) in patients undergoing parathyroidectomy for hyperparathyroidism was reported in 1988. Subse- quent improvements in the analytical performance of the rapid intraoperative PTH assay allowed the estab- lishment of its clinical utility in the surgical manage- ment of hyperparathyroidism. These modifications
Lori J. Sokoll; Frank H. Wians; Alan T. Remaley
In kidney disease, the progressive loss of renal capacity to produce calcitriol, the vitamin D hormone, is a key contributor to elevations in parathyroid hormone (PTH) and mineral and skeletal disorders predisposing to renal and cardiovascular damage, ectopic calcifications, and high mortality rates. Thus, the safe correction of calcitriol deficiency to suppress PTH has been the treatment of choice for
Adriana S Dusso; Masanori Tokumoto
Results: A total of 376 patients met the requirements for inclusion in the study. There were 275 women (73%) and 101 men (27%). Of the patients, 325 (86%) had single adenomas, 28 (7%) had double adenomas, 16 (4%) had 3 or more abnormal glands, and 1 had parathyroid cancer. There were 9 cases (2%) of persis- tent or recurrent hypercalcemia
Eric J. Bergson; Laura A. Sznyter; Sanford Dubner; Christopher J. Palestro; Keith S. Heller
A novel, electrochemiluminescence immunoassay that exclusively measures full-length parathyroid hormone (PTH), called Elecsys PTH (1-84) assay, is currently under development for clinical use. We measured serum PTH levels using this novel assay, as well as the Elecsys Intact PTH assay and the Whole PTH immunoradiometric assay, in 53 hemodialysis patients who participated in a 52-week clinical trial of cinacalcet. At baseline, serum PTH (1-84) levels measured with the Elecsys PTH (1-84) assay and those with the Whole PTH assay were comparable, and both values were significantly lower than Elecsys Intact PTH levels. After 52 weeks of cinacalcet treatment, Elecsys PTH (1-84) levels and Whole PTH levels decreased significantly by 56% and 60% from baseline, respectively. These results indicate that the Elecsys PTH (1-84) assay provides comparable data to the Whole PTH assay for monitoring parathyroid function in patients receiving hemodialysis. Introduction of this novel automated immunoassay would provide more widespread measurements of full-length PTH (1-84) in clinical practice. PMID:21595854
Tanaka, Hisae; Komaba, Hirotaka; Koizumi, Masahiro; Kakuta, Takatoshi; Fukagawa, Masafumi
[New Developments in CKD-MBD. Cell Biology of parathyroid in CKD].
Parathyroid monitors the calcium concentration in blood by signals from calcium-sensing receptors, adjusts secretion of parathyroid hormone to keep constant calcium concentration in the body. Although parathyroid parenchymal cells consist of chief cells which secrete PTH, and oxyphil cells which are rich in mitochondria, all hardly perform mitotic proliferation in normal status. However, in CKD, PTH hypersecretion and hyperplasia are started by hyperphosphatemia, hypocalcemia, and activated-vitamin-D deficiency, and the secondary hyperparathyroidism develops. While treatment with cinacalcet hydrochloride salt induced apoptosis into the parathyroid cell, a possibility of promoting the transdifferentiation to oxyphil cells from chief cells was suggested. The specific accumulation to the parathyroid of an oncotropic photosensitizer suggests the possibility of photodynamic diagnosis and treatment of hyperparathyroidism. PMID:25423925
Kakuta, Takatoshi; Sawada, Kaichiro
Bone marrow macrophages stimulate skeletal wound repair and osteoblastic bone formation by poorly defined mechanisms. Specialized proresolving mediators of inflammation drive macrophage efferocytosis (phagocytosis of apoptotic cells) and resolution, but little is known regarding this process in the bone marrow. In this study, metabololipidomic profiling via liquid chromatography mass spectrometry revealed higher levels of specialized proresolving mediators in the bone marrow relative to the spleen. The endocrine and bone anabolic agent parathyroid hormone increased specialized proresolving mediator levels, including resolvins (Rvs), in bone marrow. Human and murine primary macrophages efferocytosed apoptotic osteoblasts in vitro, and RvD1 and RvD2 (10 pM-10 nM) enhanced this process. These findings support a unique profile of specialized lipid mediators in bone marrow that contribute to a feedback system for resolution of inflammation and maintenance of skeletal homeostasis. PMID:24890726
McCauley, Laurie K; Dalli, Jesmond; Koh, Amy J; Chiang, Nan; Serhan, Charles N
Bone disease is a common disorder of bone remodeling and mineral metabolism, which affects patients with chronic kidney disease.\\u000a Minor changes in the serum level of a given mineral can trigger compensatory mechanisms, making it difficult to evaluate the\\u000a role of mineral disturbances in isolation. The objective of this study was to determine the isolated effects that phosphate\\u000a and parathyroid
Daniella G. Batista; K�tia R. Neves; Fabiana G. Graciolli; Luciene M. dos Reis; Rafael G. Graciolli; Wagner V. Dominguez; Carolina L. Neves; Andrea O. Magalh�es; Melani R. Cust�dio; Rosa M. Moys�s; Vanda Jorgetti
Parathyroid hormone-related peptide (PTHrP) was initially identified as a product of malignant tumors that mediates paraneoplastic hypercalcemia. It is now known that the parathyroid hormone (PTH) and PTHrP genes are evolutionarily related and that the products of these two genes share a common receptor, the PTH/PTHrP receptor. PTHrP and the PTH/PTHrP receptor are widely expressed in both adult and fetal tissues, and recent gene-targeting and disruption experiments have implicated PTHrP as a developmental regulatory molecule. Apparent PTHrP functions include the regulation of endochondral bone development, of hair follicle formation, and of branching morphogenesis in the breast. Herein, we report that overexpression of PTHrP in chondrocytes using the mouse type II collagen promoter induces a novel form of chondrodysplasia characterized by short-limbed dwarfism and a delay in endochondral ossification. This features a delay in chondrocyte differentiation and in bone collar formation and is sufficiently marked that the mice are born with a cartilaginous endochondral skeleton. In addition to the delay, chondrocytes in the transgenic mice initially become hypertrophic at the periphery of the developing long bones rather than in the middle, leading to a seeming reversal in the pattern of chondrocyte differentiation and ossification. By 7 weeks, the delays in chondrocyte differentiation and ossification have largely corrected, leaving foreshortened and misshapen but histologically near-normal bones. These findings confirm a role for PTHrP as an inhibitor of the program of chondrocyte differentiation. PTHrP may function in this regard to maintain the stepwise differentiation of chondrocytes that initiates endochondral ossification in the midsection of endochondral bones early in development and that also permits linear growth at the growth plate later in development. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8816783
Weir, E C; Philbrick, W M; Amling, M; Neff, L A; Baron, R; Broadus, A E
Vitamin D designates a group of calcitriols, fat solu ble hormones of secosteroid nature [1 3]. The calcitriols include vitamins D2, D3, D4, D5, and their derivatives [3]. Vitamin D3 (cholecalciferol, 4]. Vitamin D3 itself is biologi cally inert, and its bioactivation involves double hydroxy lation
Kalueff, Allan V.
Although lower vitamin D and higher parathyroid hormone (PTH) concentrations have been associated with hypertension, their independent contribution to blood pressure (BP) is unclear. The independent associations of serum 25-hydroxyvitamin D (25[OH]D) and PTH levels with BP were therefore investigated. This is a population-based cross-sectional study from the Korea National Health and Nutrition Examination Surveys, which includes a total of 4,513 participants (2,019 men and 2,494 women) aged ? 50 years. 25(OH)D and PTH were measured by radioimmunoassays, and BP was determined with a sphygmomanometer. Hypertensive subjects had significantly lower 25(OH)D (p = 0.023) and significantly higher PTH (p < 0.001) concentrations than normotensives. In subjects not taking antihypertensive medications, 25(OH)D showed reverse correlations with systolic and diastolic BP, both in men (p = 0.038-0.061 and p = 0.011-0.038, respectively) and in women (p = 0.006-0.018 and p = 0.001-0.011, respectively), while serum PTH concentrations showed positive correlations with systolic and diastolic BP in men (p = 0.001-0.014 and p < 0.001, respectively) and women (p < 0.001-0.008 and p = 0.001-0.040, respectively). When 25(OH)D and PTH were included in the same model, both remained independently associated with BP in men and women. In conclusion, both lower 25(OH)D and higher PTH may be independent factors for the development of hypertension. PMID:24114552
Kim, Hyeonmok; Chung, Yun Ey; Jung, Soo Chul; Im, Hyunjung; Yang, Seo Young; Kim, Do Young; Jeong, Eunheui; Kim, Beom; Park, Sung Ki
Background Recommendations for secondary hyperparathyroidism (SHPT) consider that a �one-size-fits-all� target enables efficacy of care. In routine clinical practice, SHPT continues to pose diagnosis and treatment challenges. One hypothesis that could explain these difficulties is that dialysis population with SHPT is not homogeneous. Methods EPHEYL is a prospective, multicenter, pharmacoepidemiological study including chronic dialysis patients (?3 months) with newly SHPT diagnosis, i.e. parathyroid hormone (PTH) ?500 ng/L for the first time, or initiation of cinacalcet, or parathyroidectomy. Multiple correspondence analysis and ascendant hierarchical clustering on clinico-biological (symptoms, PTH, plasma phosphorus and alkaline phosphatase) and treatment of SHPT (cinacalcet, vitamin D, calcium, or calcium-free calcic phosphate binder) were performed to identify distinct phenotypes. Results 305 patients (261 with incident PTH???500 ng/L; 44 with cinacalcet initiation) were included. Their mean age was 67?�?15 years, and 60% were men, 92% on hemodialysis and 8% on peritoneal dialysis. Four subgroups of SHPT patients were identified: 1/ �intermediate� phenotype with hyperphosphatemia without hypocalcemia (n?=?113); 2/ younger patients with severe comorbidities, hyperphosphatemia and hypocalcemia, despite SHPT multiple medical treatments, suggesting poor adherence (n?=?73); 3/ elderly patients with few cardiovascular comorbidities, controlled phospho-calcium balance, higher PTH, and few treatments (n?=?75); 4/ patients who initiated cinacalcet (n?=?43). The quality criterion of the model had a cut-off of 14 (>2), suggesting a relevant classification. Conclusion In real life, dialysis patients with newly diagnosed SHPT constitute a very heterogeneous population. A �one-size-fits-all� target approach is probably not appropriate. Therapeutic management needs to be adjusted to the 4 different phenotypes. PMID:25123022
Abnormal Vitamin D Metabolism and Loss of Bone Mass after Renal Transplantation
Background\\/Aim: Osteoporosis is a major complication after renal transplantation. The most important causative factor is the use of corticosteroids, but abnormalities in vitamin D metabolism and persisting hyperparathyroidism could also be involved. The present study examines changes in vitamin D metabolites, intact parathyroid hormone, and bone mineral density (BMD) during the first 2 years after renal transplantation. Methods: Sixty-one patients
Ruud G. L. de S�vaux; Andries J. Hoitsma; Harry J. C. van Hoof; Frans J. M. Corstens; Jack F. M. Wetzels
BACKGROUND: Vitamin D supplementation for fracture prevention is widespread despite conflicting interpretation of relevant randomised controlled trial (RCT) evidence. This study summarises quantitatively the current evidence from RCTs and observational studies regarding vitamin D, parathyroid hormone (PTH) and hip fracture risk. METHODS: We undertook separate meta-analyses of RCTs examining vitamin D supplementation and hip fracture, and observational studies of serum
Jeffrey K C Lai; Robyn M Lucas; Mark S Clements; Andrew W Roddam; Emily Banks
Hormone response element binding proteins: novel regulators of vitamin D and estrogen signaling
Insights from vitamin D-resistant New World primates and their human homologues as models of natural and pathological insensitivity to sterol/steroid action have uncovered a family of novel intracellular vitamin D and estrogen regulatory proteins involved in hormone action. The proteins, known as �vitamin D or estrogen response element-binding proteins�, behave as potent cis-acting, transdominant regulators to inhibit steroid receptor binding to DNA response elements and is responsible for vitamin D and estrogen resistances. This set of interactors belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family of previously known pre-mRNA-interacting proteins. This review provides new insights into the mechanism by which these novel regulators of signaling and metabolism can act to regulate responses to vitamin D and estrogen. In addition the review also describes other molecules that are known to influence nuclear receptor signaling through interaction with hormone response elements. PMID:21236284
Lisse, Thomas S.; Hewison, Martin; Adams, John S.
Molecular Structure of the Rat Vitamin D Receptor Ligand Binding Domain Complexed with 2-Carbon-Substituted Vitamin D3 Hormone Analogues and a LXXLL-Containing Coactivator Peptide, Janeen L. Vanhooke,*,| Matthew M of the ligand binding domain (LBD) of the rat vitamin D receptor in ternary complexes with a synthetic LXXLL
Pike, J. Wesley
Parathyroid hormone (PTH) caused a dramatic acceleration of erythrocyte sedimentation rate (ESR). This effect was calcium dependent and was partially reversed by verapamil. It was not mimicked by 5 mumol/l calcium ionophore A-23187. Following the removal of PTH from the cell suspension the ESR returned to normal. PTH also caused haemagglutination, the reaction was Ca2+ dependent, pH dependent and was partially reversed by verapamil. High levels of Ca2+ ionophore A-23187 mimicked this phenomenon. Magnesium ions even at concentrations of 5 mmol/l did not replace Ca2+, while Ca2+ at concentrations of 3 mmol/l and above caused haemagglutination. The glycolytic inhibitor NaF at levels of 1 mmol/l did not inhibit haemagglutination. The polyamines pertusin and spermidin, prostaglandins PGE2 and PGF, and the calcium hormone calcitonin, did not reproduce the PTH effect. Dialysate from serum of patients with chronic renal failure and hyperparathyroidism caused haemagglutination, while dialysate from patients with chronic renal failure following parathyroidectomy and normal individuals did not cause this phenomenon. It seems that abnormal erythrocyte behaviour seen in patients with chronic renal failure is caused by PTH which leads to modified Ca2+ metabolism in these cells. PMID:6661818
Earon, Y; Blum, M; Bogin, E
Expression of the PTH gene is known to be under strict tissue-specific control and is also regulated by extracellular calcium and 1,25(OH)(2)D. However, the precise mode of transcriptional regulation remains to be elucidated, because of the unavailability of appropriate cell lines derived from the parathyroid gland. We tried to identify the transcription factor(s) regulating the human PTH gene transcription using the PT-r cell line. We found that PT-r cells endogenously express PTH and several parathyroid-related genes. Using the cells, we investigated the transcriptional regulation of human PTH gene. We found that GCMB binds to the PTH gene 5'-promoter (-390/-383 bp) and positively regulates its transcription. On the other hand, 1,25(OH)(2)D(3), and, in the presence of the calcium sensing receptor, high extracellular calcium, exerted inhibitory effects on PTH gene expression. These results indicate that GCMB and vitamin D receptor are involved in the positive and negative regulation of PTH gene expression, respectively. Our data also suggest that PT-r cells retain some of the characteristics of parathyroid cells. PMID:20558332
Kawahara, Masayuki; Iwasaki, Yasumasa; Sakaguchi, Kazushige; Taguchi, Takafumi; Nishiyama, Mitsuru; Nigawara, Takeshi; Kambayashi, Machiko; Sawada, Takahiro; Jing, Xuefeng; Miyajima, Masayasu; Terada, Yoshio; Hashimoto, Kozo; Suda, Toshihoro
The reliable diagnosis of primary hyperparathyroidism de- pends on the measurement of PTH. The PTH assays in wide- spread use measure not only the hormone but also hormone fragments, thus limiting the clinical utility of the assays. A new immunoradiometric assay (IRMA) using an antigenic de- terminant at the extreme amino-terminal of the PTH molecule detects only full-length PTH (1-
Hypercalcemia is associated with gynecologic malignant diseases, and cases involving various organs such as the uterus, ovaries, vulva, and vagina. This may be due to elevated levels of parathyroid hormone-related peptide (PTHrP). We describe here two cases of ovarian carcinoma simultaneously producing PTHrP that caused hypercalcemia and metastatic calcification detected on 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT). PMID:24379537
Agarwal, Krishan Kant; Karunanithi, Sellam; Jain, Sachin; Kumar, Rakesh
The frequency of recombination between the Ggamma -globin (HBG2) and parathyroid hormone (PTH) loci on the short arm of human chromosome 11 was estimated by typing >700 single-sperm samples from two males. The sperm-typing technique employed involves the polymerase chain reaction and allele-specific oligonucleotide hybridization. Our maximum likelihood recombination fraction estimate of 0.16 (95% confidence interval, 0.13-0.19) falls well within
Xiangfeng Cui; Honghua Li; Tushar M. Goradia; Kenneth Lange; Haig H. Kazazian; David Galas; Norman Arnheim
The mechanism of inhibition of HCO3 transport by parathyroid hormone (PTH) in the proximal tubule is not clearly defined. Previous studies in vitro have suggested that this effect is mediated via cAMP generation, which acts to inhibit Na/H exchange, resulting in cell acidification. To examine this question in vivo, intracellular pH (pHi) was measured in the superficial proximal tubule of the rat using the pH-sensitive fluoroprobes 4-methylumbelliferone (4MU) and 2',7'-bis(carboxyethyl)-(5, and 6)-carboxyfluorescein (BCECF). PTH was found to alkalinize the cell. This alkalinization suggested inhibition of basolateral base exit, which was confirmed by in situ microperfusion studies: lowering HCO3 in peritubular capillaries acidified the cell, an effect blunted by PTH. Removal of luminal Na promoted basolateral base entry, alkalinizing the cell. This response was also blunted by PTH. Readdition of luminal Na stimulated the luminal Na/H exchanger, causing an alkalinization overshoot that was partially inhibited by PTH. cAMP inhibited luminal H secretion but did not alkalinize the cell. Stimulation of phosphatidylinositol-bis-phosphate turnover by PTH was suggested by the effect to the hormone to increase cell Ca. Blocking the PTH-induced rise in cell Ca blunted the effect of the hormone to alkalinize the cell, as did inhibition of phosphatidylinositol breakdown. Furthermore, stimulation of protein kinase C by a phorbol ester and a diacylglycerol applied basolaterally alkalinized the cell and inhibited luminal H secretion. The findings indicate that both arms of the phosphatidylinositol-bis-phosphate cascade play a role in mediating the effect of PTH on the cell pH. The results are consistent with the view that PTH inhibits base exit in the proximal tubule by activation of the phosphatidylinositol cascade. The resulting alkalinization may contribute, with cAMP, to inhibit apical Na/H exchange and the PTH-induced depression of proximal HCO3 reabsorption. PMID:1314850
Pastoriza-Munoz, E; Harrington, R M; Graber, M L
Vitamin D and the Immune System from the Nephrologist's Viewpoint
Vitamin D and its analogues are widely used as treatments by clinical nephrologists, especially when treating chronic kidney disease (CKD) patients with secondary hyperparathyroidism. As CKD progresses, the ability to compensate for elevations in parathyroid hormone (PTH) and fibroblast growth factor-23 and for decreases in 1,25(OH)2D3 becomes inadequate, which results in hyperphosphatemia, abnormal bone disorders, and extra-skeletal calcification. In addition to its calciotropic effect on the regulation of calcium, phosphate, and parathyroid hormone, vitamin D has many other noncalciotropic effects, including controlling cell differentiation/proliferation and having immunomodulatory effects. There are several immune dysregulations that can be noted when renal function declines. Physicians need to know well both the classical and nonclassical functions of vitamin D. This review is an analysis from the nephrologist's viewpoint and focuses on the relationship between the vitamin D and the immune system, together with vitamin's clinical use to treat kidney diseases. PMID:24587915
Wang, Min-Hui; Chiang, Chih-Kang; Lu, Kuo-Cheng
Prevalence of vitamin D insufficiency in postmenopausal south Indian women
Aim: To evaluate the dietary calcium and vitamin D status in south Indian postmenopausal women. Methods: Postmenopausal women (n=164) were evaluated for their daily dietary calcium intake, phytate to calcium ratio, and bone mineral parameters. Their serum leutinizing hormone (LH), follicle-stimulating hormone (FSH), 25-hydroxyvitamin D (25[OH]D), and parathyroid hormone levels (PTH) were measured. Results: Their age and BMI were 59.5���8
C. V. Harinarayan
Most people have four pea-sized glands, called parathyroid glands, on the thyroid gland in the neck. Though their names are similar, the thyroid and parathyroid glands are completely different. The parathyroid glands make ...
Secondary hyperparathyroidism (s-HPT) in uremia is characterized by decreased expression in the parathyroids of calcium sensing (CaR) and vitamin D receptors (VDR). Parathyroid hormone (PTH) is normalized despite low levels of CaR and VDR after experimental reversal of uremia. The expression of CaR in parathyroid cultures decreases rapidly. Methylation of promoter regions is often detected during epigenetic downregulation of gene expression. Therefore, using an experimental rat model, we examined changes in methylation levels of parathyroid CaR and VDR promoters in vivo and in vitro. Methods. Uremia was induced by 5/6 nephrectomy. Melting temperature profiling of CaR and VDR PCR products after bisulfite treatment of genomic DNA from rat parathyroids was performed. Real-time PCR measured expression of PTH, CaR, VDR, and klotho genes in vitro. Results. Parathyroids from uremic rats had similar low levels of methylation in vivo and in vitro. In culture, a significant downregulation of CaR, VDR, and klotho within two hours of incubation was observed, while housekeeping genes remained stable for 24 hours. Conclusion. In uremic s-HPT and in vitro, no overall changes in methylation levels in the promoter regions of parathyroid CaR and VDR genes were found. Thus, epigenetic methylation of these promoters does not explain decreased parathyroid expression of CaR and VDR genes in uremic s-HPT. PMID:23094155
Hofman-Bang, Jacob; Gravesen, Eva; Olgaard, Klaus; Lewin, Ewa
Alopecia areata is a common form of hair loss in which autoimmune-mediated destruction of hair follicles causes patchy hair loss, for which there is no adequate therapy. Parathyroid hormone (PTH) induces the hair cycle and promotes hair growth. PTH-CBD is a fusion protein of PTH and a bacterial collagen-binding domain (CBD), leading to targeted delivery to and retention in the skin collagen. We tested the effects of a single dose of PTH-CBD (low or high dose) on an animal model for alopecia areata, the C3H/HeJ engrafted mouse. In all the treated animals, there was a rapid (1-4 days) increase in hair growth, with sustained effects observed over a 2-month period (7/10 total treated mice<40% hair loss based on gray scale analysis, vs. 2/5 in vehicle control animals). Histological examination revealed massive stimulation of anagen VI hair follicles in treated animals despite an ongoing immune response. PTH-CBD thus shows promise as a therapy for alopecia areata, likely in conjunction with a mild immune suppressant, such as hydrocortisone cream. PMID:24326563
Katikaneni, Ranjitha; Gulati, Rohan; Suh, Daniel; Sakon, Joshua; Seymour, Andrew; Ponnapakkam, Tulasi; Gensure, Robert
The caudal neurosecretory system of the flounder (Platichthys flesus) has been examined by immunocytochemistry and in situ hybridization for the expression of parathyroid hormone-related protein (PTHrP) and calcium-sensing receptors (CaSR). The N-terminus nucleotide and deduced amino acid sequences of flounder PTHrP were determined and used to prepare oligonucleotide probes and homologous antiserum. The Dahlgren cells of the posterior spinal cord and their axons contained PTHrP protein which was also detected around the capillaries of the urophysis. PTHrP gene expression was abundant in the Dahlgren perikarya and axons in the spinal cord, but it was absent from nerve endings in the urophysis. Calcium-sensing receptor protein was present in the Dahlgren perikarya and axons, also with abundant gene expression, but there was neither protein nor mRNA in the urophysis. There were no apparent differences between freshwater- and seawater-adapted fish in either CaSR or PTHrP expression in the caudal neurosecretory system. These observations suggest that Dahlgren cells produce PTHrP which may be released from axons abutting capillaries in the urophysis. However, the sensing of ionic calcium appears to be confined to the perikarya of the Dahlgren cells in the spinal cord neuropil, suggesting that they are responsive to calcium in the central nervous system rather than the general circulation. PMID:12090395
Ingleton, PM; Bendell, LA; Flanagan, JA; Teitsma, C; Balment, RJ
GPCRs mediate intracellular signaling upon external stimuli, making them ideal drug targets. However, little is known about their activation mechanisms due to the difficulty in purification. Here, we introduce a method to purify GPCRs in nanodiscs, which incorporates GPCRs into lipid bilayers immediately after membrane solubilization, followed by single-step purification. Using this approach, we purified a family B GPCR, parathyroid hormone 1 receptor (PTH1R), which regulates calcium and phosphate homeostasis and is a drug target for osteoporosis. We demonstrated that the purified PTH1R in nanodiscs can bind to PTH(1-34) and activate G protein. We also observed that Ca2+ is a weak agonist of PTH1R and Ca2+ in millimolar concentration can switch PTH(1-34) from an inverse agonist to an agonist. Hence, our results show that nanodiscs are a viable vehicle for GPCR purification, enabling studies of GPCRs under precise experimental conditions without interference from other cellular or membrane components. PMID:23237450
Mitra, Nivedita; Liu, Yuting; Liu, Jian; Serebryany, Eugene; Mooney, Victoria; DeVree, Brian T.; Sunahara, Roger K.; Yan, Elsa C. Y.
Parathyroid hormone-related protein (PTHrP) enhances prostate cancer (CaP) growth and metastasis in vivo. PTHrP also increases cell survival and migration, and upregulates pro-invasive integrin ?6?4 expression. We used the human CaP cell lines C4-2 and PC-3 as model systems to study the mechanisms via which PTHrP regulates ?6?4 levels. We report that PTHrP regulates ?6 and ?4 levels via a transcriptional pathway; ?4 regulation involves the NF-?B pathway. PTHrP also regulates ?4 levels at the post-translational level. PTHrP inhibits caspase-3 and ?7 activities. Post-translational regulation of ?4 by PTHrP is mediated via attenuation of its proteolytic cleavage by these caspases. Since ?6 dimerizes with ?4, increased ?4 levels result in elevated ?6 levels. Suppressing ?4 using siRNA attenuates the effect of caspase inhibition on apoptosis and cell migration. These results provide evidence of a link between PTHrP, integrin ?6(34 levels as a function of caspase activity, and cell survival and migration. Targeting PTHrP in CaP cancer, thereby reversing the effect on caspase activity and ?6?4 levels, may thus prove therapeutically beneficial. PMID:23499737
Bhatia, Vandanajay; Mula, Ramanjaneya V.R.; Falzon, Miriam
Parathyroid hormone-related protein (PTHrP) enhances prostate cancer (CaP) growth and metastasis in vivo. PTHrP also increases cell survival and migration, and upregulates pro-invasive integrin ?6?4 expression. We used the human CaP cell lines C4-2 and PC-3 as model systems to study the mechanisms via which PTHrP regulates ?6?4 levels. We report that PTHrP regulates ?6 and ?4 levels via a transcriptional pathway; ?4 regulation involves the NF-?B pathway. PTHrP also regulates ?4 levels at the post-translational level. PTHrP inhibits caspase-3 and -7 activities. Post-translational regulation of ?4 by PTHrP is mediated via attenuation of its proteolytic cleavage by these caspases. Since ?6 dimerizes with ?4, increased ?4 levels result in elevated ?6 levels. Suppressing ?4 using siRNA attenuates the effect of caspase inhibition on apoptosis and cell migration. These results provide evidence of a link between PTHrP, integrin ?6?4 levels as a function of caspase activity, and cell survival and migration. Targeting PTHrP in CaP cancer, thereby reversing the effect on caspase activity and ?6?4 levels, may thus prove therapeutically beneficial. PMID:23499737
Bhatia, Vandanajay; Mula, Ramanjaneya V R; Falzon, Miriam
Introduction. This study was aimed to investigate the effects of raloxifene on intact parathyroid hormone (PTH) level and bone mineral density (BMD) for 8 months in women on hemodialysis and women with chronic kidney disease stage 5 not dependent on dialysis to determine its effect on secondary hyperparathyroidism and osteoporosis. Materials and Methods. Fifty-one women on hemodialysis and 9 with chronic kidney disease stage 5 were randomly assigned to receive oral raloxifene, 60 mg/d, or placebo for 8 months. Baseline blood determinations and BMD were done and repeated after 8 months. Serum levels of total calcium, phosphorus, alkaline phosphatase, and intact PTH were measured. Results. Serum levels of intact PTH significantly decreased in both groups, and there was no difference between the two groups after 8 months (P = .37). Serum phosphorus levels also decreased by 1.8% in the two groups. After 8 months of treatment, the BMD of the lumbar spine and femural neck decreased by 1.9% in the control group, while an increase in BMD was observed in the raloxifene group,with an average increase in both BMDs of the lumbar spine and the femural neck by 2% (significant in the lumbar spine; P = .01). Conclusions.�� Raloxifene has proven to be an effective medication in terms of improving BMD, with no adverse effects. However, it had no effect on controlling hyperparathyroidism in our patients. Long-term studies should be done to investigate the effects of raloxifene in chronic kidney disease and dialysis patients. PMID:25362221
Haghverdi, Farshid; Mortaji, Sepideh; Soltani, Parvin; Saidi, Naser; Farbodara, Tahmineh
Parathyroid hormone (PTH) and PTH-related protein (PTHrP) produce similar biological effects through the PTH/PTHrP receptor. Less is known about the physiological role of PTHrP, which was first identified as the agent of the humoral hypercalcemia of malignancy. Despite the widespread production of PTHrP in healthy individuals, the concentration of the protein is below the detectable limit of current assays, suggesting that PTHrP normally functions locally in an autocrine or paracrine manner. Thus, some differences in their biological activities have been described and they may be related to the presence of different receptors. In this regard, a second receptor that binds selectively to PTH has also been found. Recent studies have demonstrated the expression of both PTH/PTHrP receptor and protein in the renal glomeruli. Moreover, there are convincing data that support a direct role of PTH and PTHrP in modulating renal blood flow and glomerular filtration rate. This multifunctional protein, PTHrP, also has a proliferative effect on both glomerular mesangial cells and tubular epithelial cells. Increases in the expression of PTHrP have been observed in several experimental models of nephropathies, suggesting that PTHrP upregulation is a common event associated with the mechanism of renal injury and repair. PMID:11423685
Esbrit, P; Santos, S; Ortega, A; Fern�ndez-Agull�, T; V�lez, E; Troya, S; Garrido, P; Pe�a, A; Bover, J; Bosch, R J
Parathyroid hormone (PTH) plays a key role in the development and homeostasis of mineralized tissues such as bone and dentine. We have reported that PTH (1-34) administration can increase dentine formation in mice and that this hormone modulates in vitro mineralization of odontoblast-like cells. The purpose of the present study was to investigate whether PTH (1-34) participates in the proliferative and apoptotic signaling of odontoblast-like cells (MDPC23). MDPC23 cells were exposed to 50�ng/ml hPTH (1-34) or vehicle for 1 (P1), 24 (P24), or 48 (P48) hours, and the cell proliferation, apoptosis, and cell number were evaluated. To examine whether changes in the proliferative and apoptotic signaling in response to PTH involve protein kinases A (PKA) and/or C (PKC), MDPC23 cells were exposed to PTH with or without PKC or PKA signaling pathway inhibitors. Overall, the results showed that the PKA pathway acts in response to PTH exposure maintaining levels of cell proliferation, while the PKC pathway is mainly involved for longer exposure to PTH (24 or 48�h), leading to the reduction of cell proliferation and increase of apoptosis. The exposure to PTH reduced the cell number in relation to the control group in a time-dependent manner. In conclusion, PTH modulates odontoblast-like cell proliferative and apoptotic response in a time-dependent manner. Both PKC and PKA pathways participate in PTH-induced modulation in an antagonist mode. PMID:25012507
Guimar�es, Gustavo Narvaes; Rodrigues, Thais�ngela Lopes; de Souza, Ana Paula; Line, Sergio Roberto; Marques, Marcelo Rocha
Most studies of circulating PTH levels using traditional RIAs have supported the concept of physiological hyperparathyroidism of pregnancy, with pregnant women having serum immunoreactive PTH levels significantly higher than those in nonpregnant subjects. However, such RIAs are insensitive and often detect inactive PTH fragments, so that the correlation between PTH immunoreactivity and bioactivity is poor. Employing a new intact PTH immunoradiometric assay (Allegro-Nichols), we reassessed the effects of pregnancy on parathyroid function. The mean serum PTH level in 81 pregnant women was 14.4 +/- 6.3 (+/- SD) compared to 24.8 +/- 9.0 ng/L in 11 normally cycling nonpregnant women (P less than 0.001). The mean serum total and ionized calcium levels in the 2 groups were similar. In 5 of the pregnant women, serum bioactive PTH, determined by cytochemical bioassay, was slightly lower (7.7 +/- 3.4 ng/L) than in normal individuals (11.1 +/- 1.9 ng/L). Our findings suggest, in contrast with the results of most previous studies, that serum intact PTH may decline during pregnancy.
Davis, O.K.; Hawkins, D.S.; Rubin, L.P.; Posillico, J.T.; Brown, E.M.; Schiff, I.
This study assessed mitochondrial membrane potential changes in cultured osteoblasts treated with hormones known to regulate osteoblasts. A fluorescent carbocyanine dye, 5,5?, 6,6?-tetrachloro-1,1?, 3,3?-tetraethylbenzimidazolocarbocyanine iodide, also called JC-1, was used as a probe. JC-1 emits photons at 585 nm (orange�red) when the membrane potential in mitochondria is highly negative, but when the potential becomes reduced emission occurs at 527 nm
Michael B. Troyan; Virginia R. Gilman; Carol V. Gay
Association of 25-hydroxy-vitamin D levels with semen and hormonal parameters
Vitamin D levels have been linked to various health outcomes including reproductive disorders. The purpose of this study was to explore the association between serum vitamin D level (25-hydroxy-vitamin D, or 25OHD) and semen and hormonal parameters. This is a cross-sectional study that included 170 healthy men recruited for the study of spermatogenesis from the general population. Men completed general and reproductive health questionnaires, and donated blood and semen samples. The main measures were hormonal (total and free testosterone, sex hormone-binding globulin, estradiol, follicle-stimulating hormone and luteinizing hormone) and semen parameters, adjusted (n=147) for age, body mass index (BMI), season, alcohol intake and smoking, in relation to categories of vitamin D levels, determined a priori. The mean age of the study population was 29.0�8.5 years and mean BMI was 24.3�3.2�kg m?2. The mean 25OHD was 34.1�15.06�ng ml?1. BMI showed a negative association with 25OHD. Sperm concentration, sperm progressive motility, sperm morphology, and total progressively motile sperm count were lower in men with �25OHD?50�ng ml?1' when compared to men with �20 ng ml?1?25OHD<50�ng ml?1'. Total sperm count and total progressive motile sperm count were lower in men with �25OHD<20�ng ml?1' when compared to men with �20 ng ml?1?25OHD<50�ng ml?1'. The adjusted means of various hormonal parameters did not show statistical difference in the different categories of 25OHD. In conclusion, serum vitamin D levels at high and low levels can be negatively associated with semen parameters. PMID:23042450
Hammoud, Ahmad O; Wayne Meikle, A; Matthew Peterson, C; Stanford, Joseph; Gibson, Mark; Carrell, Douglas T
A randomized double-blind controlled trial of a single oral dose of 2.5 mg(100 000 IU) cholecalciferol (vitamin D3) was conducted in the winter in 189 healthy free-living men and women aged 63-76 y. The mean baseline serum concentra- tion for 25-hydroxyvitamin D was 34.5 nmolfL and for parathy- roid hormone 3.18 pmolIL. After 5 wk, mean serum 25-hydroxy- vitamin D
Kay-Tee Khaw; Robert Scragg; Sean Murphy
In addition to its basic role in the metabolism of purine nucleotides, xanthine oxidoreductase (XOR) is involved in the generation of oxygen-derived free radicals and production and metabolic fate of nitric oxide (NO). Growth hormone (GH) and Vitamin E (E) have been shown previously to modify immune response to infection. Our objective was to determine in heifers the effect of
S Kahl; T. H Elsasser
Parathyroid hormone (PTH) alters the shape of osteoblastic cells both in vivo and in vitro. In this study, we examined the effect of PTH on cytoskeletal actin and myosin, estimated by polyacrylamide gel electrophoresis of Triton X-100 (1%) nonextractable proteins. After 2-5 minutes, PTH caused a rapid and transient decrease of 50-60% in polymerized actin and myosin associated with the Triton X-100 nonextractable cytoskeleton. Polymerized actin returned to control levels by 30 min. The PTH effect was dose-dependent with an IC50 of about 1 nM, and was partially inhibited by the (3-34) PTH antagonist. PTH caused a rapid transient rise in cyclic AMP (cAMP) in these cells that peaked at 4 min, while the nadir in cytoskeletal actin and myosin was recorded around 5 min. The intracellular calcium chelator Quin-2/AM (10 microM) also decreased cytoskeletal actin and myosin, to the same extent as did PTH (100 nM). To distinguish between cAMP elevation and Ca++ reduction as mediators of PTH action, we measured the phosphorylation of the 20 kD (PI 4.9) myosin light chain in cells preincubated with (32P)-orthophosphate. The phosphorylation of this protein decreased within 2-3 min after PTH addition and returned to control levels after 5 min. The calcium ionophore A-23187 did not antagonize this PTH effect. Visualization of microfilaments with rhodamine-conjugated phalloidin showed that PTH altered the cytoskeleton by decreasing the number of stress fibers. These changes in the cytoskeleton paralleled changes in the shape of the cells from a spread configuration to a stellate form with retracting processes. The above findings indicate that the alteration in osteoblast shape produced by PTH involve relatively rapid and transient changes in cytoskeletal organization that appear to be mediated by cAMP.
Egan, J.J.; Gronowicz, G.; Rodan, G.A. (National Institutes of Diabetes, Digestive, and Kidney Diseases, Bethesda, MD (USA))
The human parathyroid hormone type 2 receptor (PTH2R) is activated by PTH and by tuberoinfundibular peptide of 39 residues (TIP39), the latter likely acting as its natural ligand. Although the receptor is expressed at highest levels in the nervous system, we have observed that both PTH2R and TIP39 are expressed in the newborn mouse growth plate, with the receptor localizing in the resting zone and the ligand TIP39 localizing exclusively in prehypertrophic and hypertrophic chondrocytes. To address the role of PTH2R in postnatal skeletal growth and development, Col2a1-hPTH2R (PTH2R-Tg) transgenic mice were generated. The mice were viable and of nearly normal size at birth. Expression of the transgene in the growth plate was limited to chondrocytes. We found that chondrocyte proliferation was decreased, as determined by in vivo BrdU labeling of proliferating chondrocytes and CDK4 and p21 expression in the growth plate of Col2a1-hPTH2R transgenic mice. Similarly, the differentiation and maturation of chondrocytes was delayed, as characterized by decreased Sox9 expression and weaker immunostaining for the chondrocyte differentiation markers collagen type II and type X and proteoglycans. As well, there was altered expression of Gdf5, Wdr5, and ?-catenin, factors implicated in chondrocyte maturation, proliferation, and differentiation.These effects impacted on the process of endochondral ossification, resulting in delayed formation of the secondary ossification center, and diminished trabecular bone volume. The findings substantiate a role for PTH2R signaling in postnatal growth plate development and subsequent bone mass acquisition. PMID:23092913
Panda, Dibyendu Kumar; Goltzman, David
NASA Technical Reports Server (NTRS)
Skeletal unloading decreases bone formation and osteoblast number in vivo and decreases the number and proliferation of bone marrow osteoprogenitor (BMOp) cells in vitro. We tested the ability of parathyroid hormone (PTH) to stimulate BMOp cells in vivo by treating Sprague Dawley rats (n = 32) with intermittent PTH(1-34) (1 h/day at 8 microg/100 g of body weight), or with vehicle via osmotic minipumps during 7 days of normal weight bearing or hind limb unloading. Marrow cells were flushed from the femur and cultured at the same initial density for up to 21 days. PTH treatment of normally loaded rats caused a 2.5-fold increase in the number of BMOp cells, with similar increases in alkaline phosphatase (ALP) activity and mineralization, compared with cultures from vehicle-treated rats. PTH treatment of hind limb unloaded rats failed to stimulate BMOp cell number, ALP activity, or mineralization. Hind limb unloading had no significant effect on PTH receptor mRNA or protein levels in the tibia. Direct in vitro PTH challenge of BMOp cells isolated from normally loaded bone failed to stimulate their proliferation and inhibited their differentiation, suggesting that the in vivo anabolic effect of intermittent PTH on BMOp cells was mediated indirectly by a PTH-induced factor. We hypothesize that this factor is insulin-like growth factor-I (IGF-I), which stimulated the in vitro proliferation and differentiation of BMOp cells isolated from normally loaded bone, but not from unloaded bone. These results suggest that IGF-I mediates the ability of PTH to stimulate BMOp cell proliferation in normally loaded bone, and that BMOp cells in unloaded bone are resistant to the anabolic effect of intermittent PTH therapy due to their resistance to IGF-I.
Kostenuik, P. J.; Harris, J.; Halloran, B. P.; Turner, R. T.; Morey-Holton, E. R.; Bikle, D. D.
We investigated the roles of interleukin-6 (IL-6) and parathyroid hormone-related peptide (PTHrP) in oral squamous cell carcinoma (OSCC)-induced osteoclast formation. Microarray analyses performed on 43 human OSCC specimens revealed that many of the specimens overexpressed PTHrP mRNA, but a few overexpressed IL-6 mRNA. Immunohistochemical analysis revealed that IL-6 was expressed not only in cancer cells but also in fibroblasts and osteoclasts at the tumor-bone interface. Many of the IL-6-positive cells coexpressed vimentin. Conditioned medium (CM) derived from the culture of oral cancer cell lines (BHY, Ca9-22, HSC3, and HO1-u-1) stimulated Rankl expression in stromal cells and osteoclast formation. Antibodies against both human PTHrP and mouse IL-6 receptor suppressed Rankl in ST2 cells and osteoclast formation induced by CM from BHY and Ca9-22, although the inhibitory effects of IL6 antibody were greater than those of PTHrP antibody. CM derived from all of the OSCC cell lines effectively induced IL-6 expression in stromal cells, and the induction was partially blocked by anti-PTHrP antibody. Xenografts of HSC3 cells onto the periosteal region of the parietal bone in athymic mice presented histology and expression profiles of RANKL and IL-6 similar to those observed in bone-invasive human OSCC specimens. These results indicate that OSCC provides a suitable microenvironment for osteoclast formation not only by producing IL-6 and PTHrP but also by stimulating stromal cells to synthesize IL-6. PMID:20035059
Kayamori, Kou; Sakamoto, Kei; Nakashima, Tomoki; Takayanagi, Hiroshi; Morita, Kei-ichi; Omura, Ken; Nguyen, Su Tien; Miki, Yoshio; Iimura, Tadahiro; Himeno, Akiko; Akashi, Takumi; Yamada-Okabe, Hisafumi; Ogata, Etsuro; Yamaguchi, Akira
Summary Because of recent insights into the pathogenesis of age-related bone loss, we investigated whether intermittent parathyroid hormone (PTH) administration antagonizes the molecular mechanisms of the adverse effects of aging on bone. PTH produced a greater increase in vertebral trabecular bone mineral density and bone volume as well as a greater expansion of the endocortical bone surface in the femur of 26 as compared to 6 month old female C57BL/6 mice. Moreover, PTH increased trabecular connectivity in vertebrae and the toughness of both vertebrae and femora in old, but not young, mice. PTH also increased the rate of bone formation and reduced osteoblast apoptosis to a greater extent in the old mice. Most strikingly, PTH reduced reactive oxygen species (ROS), p66Shc phosphorylation and expression of the lipoxygenase Alox15; and it increased glutathione and stimulated Wnt signaling in bone of old mice. PTH also antagonized the effects of oxidative stress on p66Shc phosphorylation, FoxO transcriptional activity, osteoblast apoptosis, and Wnt signaling in vitro. In contrast, administration of the antioxidants N-acetyl cysteine or pegylated catalase reduced osteoblast progenitors, and attenuated proliferation and Wnt signaling. These results suggest that PTH has a greater bone anabolic efficacy in old age because in addition to its other positive actions on bone formation it antagonizes the age-associated increase in oxidative stress and its adverse effects on the birth and survival of osteoblasts. On the other hand, ordinary antioxidants cannot restore bone mass in old age because they slow remodeling and attenuate osteoblastogenesis by interfering with Wnt signaling. PMID:20698835
Jilka, R.L.; Almeida, M.; Ambrogini, E.; Han, L.; Roberson, P. K.; Weinstein, R.S.; Manolagas, S.C.
NASA Technical Reports Server (NTRS)
Parathyroid hormone (PTH) is a potent anabolic agent for bone, but the mechanism(s) by which it works remains imperfectly understood. Previous studies have indicated that PTH stimulates insulin-like growth factor (IGF) I production, but it remains uncertain whether IGF-I mediates some or all of the skeletal actions of PTH. To address this question, we examined the skeletal response to PTH in IGF-I-deficient (knockout [k/o]) mice. These mice and their normal littermates (NLMs) were given daily injections of PTH (80 microg/kg) or vehicle for 2 weeks after which their tibias were examined for fat-free weight (FFW), bone mineral content, bone structure, and bone formation rate (BFR), and their femurs were assessed for mRNA levels of osteoblast differentiation markers. In wild-type mice, PTH increased FFW, periosteal BFR, and cortical thickness (C.Th) of the proximal tibia while reducing trabecular bone volume (BV); these responses were not seen in the k/o mice. The k/o mice had normal mRNA levels of the PTH receptor and increased mRNA levels of the IGF-I receptor but markedly reduced basal mRNA levels of the osteoblast markers. Surprisingly, these mRNAs in the k/o bones increased several-fold more in response to PTH than the mRNAs in the bones from their wild-type littermates. These results indicate that IGF-I is required for the anabolic actions of PTH on bone formation, but the defect lies distal to the initial response of the osteoblast to PTH.
Bikle, Daniel D.; Sakata, Takeshi; Leary, Colin; Elalieh, Hashem; Ginzinger, David; Rosen, Clifford J.; Beamer, Wesley; Majumdar, Sharmila; Halloran, Bernard P.
Bioactive lipids initiate inflammatory reactions leading to pathogenesis of atherosclerosis. Evidence shows that they also contribute to bone loss by inhibiting parathyroid hormone receptor (PTH1R) expression and differentiation of osteoblasts. We previously demonstrated that bone anabolic effects of PTH(1-34) are blunted in hyperlipidemic mice and that these PTH effects are restored by antioxidants. However, it is not clear which osteoblastic cell developmental stage is targeted by bioactive lipids. To investigate the effects of hyperlipidemia at the cellular level, hyperlipidemic Ldlr(-/-) mice were bred with Col3.6GFPtpz mice, in which preosteoblasts/osteoblasts carry a topaz fluorescent label, and with Col2.3GFPcyan mice, in which more mature osteoblasts/osteocytes carry a cyan fluorescent label. Histological analyses of trabecular bone surfaces in femoral as well as calvarial bones showed that intermittent PTH(1-34) increased fluorescence intensity in WT-Tpz mice, but not in Tpz-Ldlr(-/-) mice. In contrast, PTH(1-34) did not alter fluorescence intensity in femoral cortical envelopes of either WT-Cyan or Ldlr(-/-)-Cyan mice. To test the mechanism of PTH1R downregulation, preosteoblastic MC3T3-E1 cells were treated with bioactive lipids and the antioxidant Trolox. Results showed that inhibitory effects of PTH1R levels by bioactive lipids were rescued by pretreatment with Trolox. The inhibitory effects on expression of PTH1R as well as on PTH-induced osteoblastic genes were mimicked by xanthine/xanthine oxidase, a known generator of reactive oxygen species. These findings suggest an important role of the preosteoblastic development stage as the target and downregulation of PTH receptor expression mediated by intracellular oxidant stress as a mechanism in hyperlipidemia-induced PTH resistance. PMID:24038594
Li, Xin; Garcia, Jamie; Lu, Jinxiu; Iriana, Sidney; Kalajzic, Ivo; Rowe, David; Demer, Linda L; Tintut, Yin
Mediastinal parathyroid tumors.
Mediastinal parathyroid tumors are a frequent cause of failed parathyroid operations. I therefore reviewed my experience with 285 consecutive patients treated surgically for hyperparathyroidism from January 1981 to Dec 31, 1986. Two hundred eighty-eight operations were performed on these patients (246 primary, 38 secondary, one error in diagnosis, and 53 reoperations). Mediastinal parathyroid tumors were present in 64 (22%) of the entire group of 285 patients with hyperparathyroidism, and 20 (38%) of 53 patients requiring reoperation for persistent or recurrent hyperparathyroidism. Fifty-two parathyroid tumors were situated in the anterior mediastinum and 12 were found in the posterior mediastinum; 56 of the mediastinal tumors were removed via a cervical approach. In four patients the mediastinal tumor was a fifth histologically documented parathyroid gland. Mediastinal tumors were identified by preoperative localization studies (ultrasonography, three [16%]; thallium-technetium, five of 17 [29%]; computed tomography, eight of 14 [57%]; magnetic resonance imaging, three of seven [43%]; and selective venous catheterization for parathyroid hormone, ten of 11 [91%]). Awareness of the relatively high occurrence of mediastinal tumors (52 anterior, 12 posterior) should decrease the risk of failed parathyroid operations. PMID:3415460
Clark, O H
Parathyroid hormone-related peptide (PTHrP) appears to play a major role in skeletal devel- opment. Targeted disruption of the PTHrP gene in mice causes skeletal dysplasia with accelerated chon- drocyte maturation (Amizuka, N., H. Warshawsky, J.E. Henderson, D. Goltzman, and A.C. Karaplis. 1994. J. Cell Biol. 126:1611-1623; Karaplis, A.C., A. Luz, J. Glowacki, R.T. Bronson, V.L.J. Tybulewicz, H.M. Kronenberg, and R.C.
Michael Amling; Lynn Neff; Sakae Tanaka; Daisuke Inoue; Keisuke Kuida; Eleanor Weir; William M. Philbrick; Arthur E. Broadus; Roland Baron
:�� Osteoporosis in men is a significant health problem, and factors associated with bone mass are being investigated. Although\\u000a osteoporosis is a typical feature of hypogonadism, the influence of testosterone levels and other hormonal factors on bone\\u000a mass of eugonadal males is unknown. Our aim was to identify several anthropometric and hormonal predictors that could be responsible\\u000a for the variability
G. Mart�nez D�az-Guerra; F. Hawkins; A. Rapado; M. A. Ruiz D�az; M. D�az-Curiel
Alkylating Derivatives of Vitamin D Hormone for Prostate Cancer.
National Technical Information Service (NTIS)
Prostate cancer (PCa) is the most prevalent cancer among men, and second leading cause of cancer death among men in the US. Current clinical interventions for PCa include surgery and radiation therapy, and anti-hormone and androgen-deprivation therapy for...
R. Ray
. Neurosteroid hormone vitamin D and its utility in clinical nutrition Allan V. Kalueffa and Pentti Tuohimaab Purpose of review Vitamin D is a seco-steroid hormone with multiple functions in the nervous system. We discuss clinical and experimental evidence of the role of vitamin D in normal and pathological brain
Kalueff, Allan V.
Background The biological mechanisms in the association between the metabolic syndrome (MS) and various biomarkers, such as 25-hydroxyvitamin D (vit D) and magnesium, are not fully understood. Several of the proposed predictors of MS are also possible predictors of parathyroid hormone (PTH). We aimed to explore whether PTH is a possible mediator between MS and various possible explanatory variables in morbidly obese patients. Methods Fasting serum levels of PTH, vit D and magnesium were assessed in a cross-sectional study of 1,017 consecutive morbidly obese patients (68% women). Dependencies between MS and a total of seven possible explanatory variables as suggested in the literature, including PTH, vit D and magnesium, were specified in a path diagram, including both direct and indirect effects. Possible gender differences were also included. Effects were estimated using Bayesian path analysis, a multivariable regression technique, and expressed using standardized regression coefficients. Results Sixty-eight percent of the patients had MS. In addition to type 2 diabetes and age, both PTH and serum phosphate had significant direct effects on MS; 0.36 (95% Credibility Interval (CrI) [0.15, 0.57]) and 0.28 (95% CrI [0.10,0.47]), respectively. However, due to significant gender differences, an increase in either PTH or phosphate corresponded to an increased OR for MS in women only. All proposed predictors of MS had significant direct effects on PTH, with vit D and phosphate the strongest; -0.27 (95% CrI [-0.33,-0.21]) and -0.26 (95% CrI [-0.32,-0.20]), respectively. Though neither vit D nor magnesium had significant direct effects on MS, for women they both affected MS indirectly, due to the strong direct effect of PTH on MS. For phosphate, the indirect effect on MS, mediated through serum calcium and PTH, had opposite sign than the direct effect, resulting in the total effect on MS being somewhat attenuated compared to the direct effect only. Conclusion Our results indicate that for women PTH is a plausible mediator in the association between MS and a range of explanatory variables, including vit D, magnesium and phosphate. PMID:21306649
The nuclear vitamin D receptor (VDR) binds the 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] hormone with high affinity and elicits its actions to regulate gene expression in target cells by binding to vitamin D-responsive elements (VDREs). VDREs in positively controlled genes such as osteocalcin, osteopontin, ?3-integrin, and vitamin D-24-OHase are direct hexanucleotide repeats with a spacer of three nucleotides. The VDR associates with
M. R. Haussler; P. W. Jurutka; J.-C. Hsieh; P. D. Thompson; S. H. Selznick; C. A. Haussler; G. K. Whitfield
Objective: The positive short-term effects of postmenopausal hormone replacement therapy (HRT) on serum lipids are well known, but it has been suggested that they vanish with time. Cholecalciferol (vitamin D3) is widely used to prevent postmenopausal osteoporosis but the influence of vitamin D3 on serum lipids is poorly known. The long-term effects of HRT and vitamin D3 on the concentrations
Anna-Mari Heikkinen; Marjo T Tuppurainen; Leo Niskanen; Marja Komulainen; Ilkka Penttila; Seppo Saarikoski
Defects in bone regulatory pathways have been linked to chronic diseases including cardiovascular disease and cancer. In men, a link between bone metabolism and gonadal hormones has been suggested. However, to date, there is lack of evidence on the association between serum inorganic phosphate (Pi) and sex steroid hormones. The objective of this study was to investigate the association between Pi, sex steroid hormones and a known Pi metabolic regulator, vitamin D, in men in the National Health and Nutrition Examination Survey III (NHANES III). From NHANES III, we selected 1412 men aged 20+ who participated in the morning session of Phase I (1988-1991) with serum measurements of Pi, sex hormones, and vitamin D. Multivariable linear regression was used to calculate crude and geometric mean Pi by total and estimated free testosterone and estradiol, sex hormone-binding globulin, androstanediol glucuronide (AAG), and vitamin D. Similar analyses were performed while stratifying by race/ethnicity and vitamin D levels. We found a lack of statistically significant difference in geometric means of Pi across quintiles of concentrations of sex hormones, indicating a tight regulation of Pi. However, Pi levels were inversely associated with calculated free testosterone in non-Hispanic black men, with geometric mean levels of Pi of 1.16 and 1.02�ng/mL for those in the lowest and highest quintiles of free testosterone, respectively (p-trend�<�0.05). A similar but weaker pattern was seen between total testosterone and Pi. An inverse association was also seen between AAG and Pi in men with vitamin D concentration below the median (<24.2�ng/mL). No associations were observed among men with vitamin D levels at or above the median. Our findings suggest a weak link among sex hormones, vitamin D, and Pi in men. The observed effects of race/ethnicity and vitamin D indicate a complex association involving various regulators of Pi homeostasis. PMID:25270590
Wulaningsih, W; Van Hemelrijck, M; Michaelsson, K; Kanarek, N; Nelson, W G; Ix, J H; Platz, E A; Rohrmann, S
Parathyroid hormone-related protein (PTHrP) plays an important role in regulating embryonic skeletal development and is abnormally regulated in the pathogenesis of skeletal complications observed with many cancers and osteoporosis. It exerts its action through binding to a G-protein-coupled seven-transmembrane cell-surface receptor (GPCR). Structurally, GPCRs are very difficult to study by X-ray crystallography. In this study, a monoclonal antibody Fab fragment which recognizes the same region of PTHrP as its receptor, PTH1R, was used to aid in the crystallization of PTHrP. The resultant protein complex was crystallized using the hanging-drop vapour-diffusion method with polyethylene glycol as a precipitant. The crystals belonged to the orthorhombic space group P2{sub 1}2{sub 1}2, with unit-cell parameters a = 72.6, b = 96.3, c = 88.5 {angstrom}, and diffracted to 2.0 {angstrom} resolution using synchrotron radiation. The crystal structure will shed light on the nature of the key residues of PTHrP that interact with the antibody and will provide insights into how the antibody is able to discriminate between PTHrP and the related molecule parathyroid homone.
McKinstry, William J.; Polekhina, Galina; Diefenbach-Jagger, Hannelore; Sato, Koh; Onuma, Etsuro; Gillespie, Matthew T.; Martin, Thomas J.; Parker, Michael W.; (SVIMR-A); (Chugai); (Melbourne)
Renal handling of Na and Ca in response to physiological saline infusion (20 ml/kg i.v. for 2 h) was compared between 27 hypertensive (mean +/- SD age 79.8 +/- 9.2 years) and 44 normotensive (79.1 +/- 4.1 years) senile females. Compared to the normotensive group, the hypertensive group showed statistically significant decreases in the basal values of serum Ca and PRA, and significant increases in basal circulating levels of parathyroid hormone and 1,25(OH)2D and in urinary excretions of Na, Ca and Pi in the 2-hour urine specimens during the saline infusion. These results suggest that the excessive excretions of Ca and Pi associated with exaggerated natriuresis may participate in aberration of Ca metabolism in low-renin hypertensive seniles. PMID:1959361
Morimoto, S; Imaoka, M; Kitano, S; Imanaka, S; Fukuo, K; Miyashita, Y; Koh, E; Ogihara, T
Objectives: To analyze the predictive values of selec- tive venous sampling (SVS) in our own experience and in a systematic meta-analysis of the international litera- ture and to compare them with the results of noninva- sive localization studies before reoperative parathyroid surgery. Data Sources: Twenty-one consecutive patients with persistent or recurrent renal hyperparathyroidism un- derwentpreoperativeSVSandnoninvasiveimaging.These data were added to a
Daniel Seehofer; Thomas Steinm�ller; Nada Rayes; Peter Podrabsky; Julia Riethm�ller; Jochen Klupp; Frank Ulrich; Ralph Schindler; Ulrich Frei; Peter Neuhaus
Objective To determine the cause of refractory hypercalcemia in a patient with metastatic renal cell carcinoma. Methods We describe the clinical, pathologic, and immunostain findings in a patient with metastatic renal cell carcinoma and hypercalcemia of malignancy refractory to intravenous bisphosphonates. Results A 57-year-old man with a remote history of clear cell renal cell carcinoma was referred to our clinic for evaluation of resistant hypercalcemia 12 years after nephrectomy. The patient had simultaneous elevation of serum 1,25-dihydroxyvitamin D and parathyroid hormone�related peptide. Computed tomographic scan of the chest and abdomen demonstrated numerous ring-enhancing lesions in the liver, and histologic examination of a biopsy specimen revealed liver tissue infiltrated by a malignant neoplasm composed of cells with clear and eosinophilic cytoplasm, arranged in tubules and nests. Findings were morphologically consistent with renal cell carcinoma of clear cell type, and positive immunostaining with the epithelial markers EMA and CAM 5.2 were supportive of the morphologic impression of renal cell carcinoma. The tumor showed expression of 25-hydroxyvitamin D 1?-hydroxylase by immunostaining. After failing to respond to intravenous bisphosphonates, the hypercalcemia improved with prednisone treatment. Conclusions In some patients with renal cell carcinoma, hypercalcemia of malignancy is associated with simultaneous elevation in serum 1,25-dihydroxyvitamin D and parathyroid hormone�related peptide. As our case exemplifies, it is imperative to identify such patients because hypercalcemia due to elevated 1,25-dihydroxyvitamin D levels may respond better to glucocorticoid treatment than to the conventional management with bisphosphonates. PMID:19364692
Shivnani, Sarika B.; Shelton, John M.; Richardson, James A.; Maalouf, Naim M.
The calcium-sensing receptor (CaR) is a G-protein-coupled receptor that signals in response to extracellular calcium and regulates parathyroid hormone secretion. The CaR is also expressed on normal mammary epithelial cells (MMECs), where it has been shown to inhibit secretion of parathyroid hormone-related protein (PTHrP) and participate in the regulation of calcium and bone metabolism during lactation. In contrast to normal breast cells, the CaR has been reported to stimulate PTHrP production by breast cancer cells. In this study, we confirmed that the CaR inhibits PTHrP production by MMECs but stimulates PTHrP production by Comma-D cells (immortalized murine mammary cells) and MCF-7 human breast cancer cells. We found that changes in intracellular cAMP, but not phospholipase C or MAPK signaling, correlated with the opposing effects of the CaR on PTHrP production. Pharmacologic stimulation of cAMP accumulation increased PTHrP production by normal and transformed breast cells. Inhibition of protein kinase A activity mimicked the effects of CaR activation on inhibiting PTHrP secretion by MMECs and blocked the effects of the CaR on stimulating PTHrP production in Comma-D and MCF-7 cells. We found that the CaR coupled to G?i in MMECs but coupled to G?s in Comma-D and MCF-7 cells. Thus, the opposing effects of the CaR on PTHrP production are because of alternate G-protein coupling of the receptor in normal versus transformed breast cells. Because PTHrP contributes to hypercalcemia and bone metastases, switching of G-protein usage by the CaR may contribute to the pathogenesis of breast cancer. PMID:18621740
Mamillapalli, Ramanaiah; VanHouten, Joshua; Zawalich, Walter; Wysolmerski, John
Impaired Vitamin D Metabolism in CKD
Vitamin D metabolism consists of both production and catabolism, which are enzymatically driven and highly regulated. Renal vitamin D metabolism requires filtration and tubular reabsorption of 25-hydroxyvitamin D and is regulated by parathyroid hormone, fibroblast growth factor-23, and 1,25-dihydroxyvitamin D. In CKD, renal production of1,25-dihydroxyvitamin D from 25-hydroxyvitamin D is reduced. In addition, pharmacokinetic studies and epidemiologic studies of 24,25-dihydroxyvitamin D, the most abundant product of 25-hydroxyvitamin D catabolism by CYP24A1, suggest that vitamin D catabolism is also reduced. New insights into the mechanisms and regulation of vitamin D metabolism may lead to novel approaches to assess and treat impaired vitamin D metabolism in CKD. PMID:23465502
Bosworth, Cortney; de Boer, Ian H.
There is growing recognition that traumatic brain injury (TBI) is a highly variable and complex systemic disorder that is refractory to therapies that target individual mechanisms. It is even more complex in the elderly, in whom frailty, prior comorbidities, altered metabolism, and a long history of medication use are likely to complicate the secondary effects of brain trauma. Progesterone, one of the few neuroprotective agents that has shown promise for the treatment of acute brain injury, is now in national and international Phase III multi-center trial. New findings show that vitamin D hormone (VDH) and vitamin D deficiency in aging (and across the developmental spectrum) may interact with progesterone and TBI treatment. This paper reviews the use of progesterone and VDH as biologics based therapies and recent studies showing that the combination of progesterone and VDH may promote better functional outcomes than either treatment independently. PMID:21703565
Stein, Donald G.; Cekic, Milos M.
Vitamin D-Binding Protein and Vitamin D Status of Black Americans and White Americans
Background Low levels of total 25-hydroxyvitamin D are common among black Americans. Vitamin D�binding protein has not been considered in the assessment of vitamin D deficiency. Methods In the Healthy Aging in Neighborhoods of Diversity across the Life Span cohort of blacks and whites (2085 participants), we measured levels of total 25-hydroxyvitamin D, vitamin D�binding protein, and parathyroid hormone as well as bone mineral density (BMD). We genotyped study participants for two common polymorphisms in the vitamin D�binding protein gene (rs7041 and rs4588). We estimated levels of bioavailable 25-hydroxyvitamin D in homozygous participants. Results Mean (�SE) levels of both total 25-hydroxyvitamin D and vitamin D�binding protein were lower in blacks than in whites (total 25-hydroxyvitamin D, 15.6�0.2 ng per milliliter vs. 25.8�0.4 ng per milliliter, P<0.001; vitamin D�binding protein, 168�3 ?g per milliliter vs. 337�5 ?g per milliliter, P<0.001). Genetic polymorphisms independently appeared to explain 79.4% and 9.9% of the variation in levels of vitamin D�binding protein and total 25-hydroxyvitamin D, respectively. BMD was higher in blacks than in whites (1.05�0.01 g per square centimeter vs. 0.94�0.01 g per square centimeter, P<0.001). Levels of parathyroid hormone increased with decreasing levels of total or bioavailable 25-hydroxyvitamin D (P<0.001 for both relationships), yet within each quintile of parathyroid hormone concentration, blacks had significantly lower levels of total 25-hydroxyvitamin D than whites. Among homozygous participants, blacks and whites had similar levels of bioavailable 25-hydroxy vitamin D overall (2.9�0.1 ng per milliliter and 3.1�0.1 ng per milliliter, respectively; P = 0.71) and within quintiles of parathyroid hormone concentration. Conclusions Community-dwelling black Americans, as compared with whites, had low levels of total 25-hydroxyvitamin D and vitamin D�binding protein, resulting in similar concentrations of estimated bioavailable 25-hydroxyvitamin D. Racial differences in the prevalence of common genetic polymorphisms provide a likely explanation for this observation. (Funded by the National Institute on Aging and others.) PMID:24256378
Powe, Camille E.; Evans, Michele K.; Wenger, Julia; Zonderman, Alan B.; Berg, Anders H.; Nalls, Michael; Tamez, Hector; Zhang, Dongsheng; Bhan, Ishir; Karumanchi, S. Ananth; Powe, Neil R.; Thadhani, Ravi
The purpose of the present study was to determine whether vitamin K2 and growth hormone (GH) had an additive effect on the long bones in hypophysectomized young rats. Forty-eight female Sprague�Dawley\\u000a rats (6 weeks old) were assigned to the following five groups by the stratified weight randomization method: intact controls,\\u000a hypophysectomy (HX) alone, HX + vitamin K2 (30?mg\\/kg, p.o., daily),
Jun Iwamoto; Tsuyoshi Takeda; Yoshihiro Sato; James K. Yeh
Doxercalciferol, a pro-hormone of Vitamin D, prevents the development of cardiac hypertrophy in rats
Background Activated vitamin D analog, paricalcitol, has been shown to attenuate the development of cardiac hypertrophy in Dahl salt sensitive (DSS) rats. To determine whether an anti-hypertrophic effect is class specific, we tested if doxercalciferol (a pro-hormone vitamin D2 analog) could also attenuate the development of cardiac hypertrophy in DSS rats. Methods and Results Male DSS rats were fed a high salt (HS) diet for 6 weeks beginning at 6 weeks of age. Doxercalciferol was administered intraperitoneally (i.p.) at 150ng, 3 times a week (Mon, Wed, Fri) for six weeks. Pathological and echocardiographic findings demonstrated that rats on HS diet with doxercalciferol administration had significant decrease in cardiac hypertrophy and improved cardiac function compared to the HS + vehicle. In addition, there was a significant decrease in plasma brain natriuretic peptide (BNP) level and tissue atrial natriuretic factor (ANF) mRNA level with doxercalciferol treatment. Doxercalciferol also significantly reduced the level of protein kinase C-? (PKC?) suggesting that PKC-mediated cardiac hypertrophy may be associated with vitamin D deficiency. Conclusions Administration of doxercalciferol attenuated the development of HS diet induced cardiac hypertrophy and cardiac dysfunction in DSS rats. PMID:22123370
Choi, Jun H.; Ke, Qingen; Bae, Soochan; Lee, Ji Yoo; Kim, Yu Jin; Kim, Ui Kyoung; Arbeeny, Cynthia; Thadhani, Ravi; Kang, Peter M.
To evaluate the potential use of a combination of parathyroid hormone (PTH) and estrogen as therapy for osteoporosis, we examined the effects of combined and separate administration of low-dose PTH and estradiol in ovariectomized rats with established osteopenia. Ovariectomized rats were untreated for 5 weeks after surgery and then injected s.c. with vehicle (Ovx+V), 1�34 hPTH (2.5 �g\\/kg\\/day) (Ovx+P), 17�-estradiol
V. Shen; D. W. Dempster; R. W. E. Mellish; R. Birchman; W. Horbert; R. Lindsay
In mammals, parathyroid hormone-related peptide (PTHrP, alias PTH-like hormone (Pthlh)) acts as a paracrine hormone that regulates the patterning of cartilage, bone, teeth, pancreas, and thymus. Beyond mammals, however, little is known about the molecular genetic mechanisms by which Pthlh regulates early development. To evaluate conserved pathways of craniofacial skeletogenesis, we isolated two Pthlh co-orthologs from the zebrafish (Danio rerio) and investigated their structural, phylogenetic, and syntenic relationships, expression, and function. Results showed that pthlh duplicates originated in the teleost genome duplication. Zebrafish pthlha and pthlhb were maternally expressed and showed overlapping and distinct zygotic expression patterns during skeletal development that mirrored mammalian expression domains. To explore the regulation of duplicated pthlh genes, we studied their expression patterns in mutants and found that both sox9a and sox9b are upstream of pthlha in arch and fin bud cartilages, but only sox9b is upstream of pthlha in the pancreas. Morpholino antisense knockdown showed that pthlha regulates both sox9a and sox9b in the pharyngeal arches but not in the brain or otic vesicles and that pthlhb does not regulate either sox9 gene, which is likely related to its highly degraded nuclear localization signal. Knockdown of pthlha but not pthlhb caused runx2b overexpression in craniofacial cartilages and premature bone mineralization. We conclude that in normal cartilage development, sox9 upregulates pthlh, which downregulates runx2, and that the duplicated nature of all three of these genes in zebrafish creates a network of regulation by different co-orthologs in different tissues. PMID:22761277
Yan, Yi-Lin; Bhattacharya, Poulomi; He, Xin Jun; Ponugoti, Bhaskar; Marquardt, Ben; Layman, Jason; Grunloh, Melissa; Postlethwait, John H.; Rubin, David A.
Vitamin D Status During Puberty in French Healthy Male Adolescents
:�� The vitamin D status was determined on one to four occasions either after summer (September�October) or after winter (March�April)\\u000a in 175 male adolescents (13�17 years), resulting in 394 measurements of serum 25-hydroxyvitamin D (25(OH)D) and intact parathyroid\\u000a hormone (iPTH). The subjects lived in a rural area to the north of Paris (49? N). After summer the 25(OH)D concentration was
J. Guillemant; P. Taupin; H. T. Le; N. Taright; A. Allemandou; G. P�r�s; S. Guillemant
NSDL National Science Digital Library
This site describes a study sponsored by the National Heart, Lung, and Blood Institute, which found that postmenopausal women with heart disease did not benefit from high doses of antioxidants vitamins, whether alone or in combination with hormone replacement therapy. In fact, researchers found both treatments to be potentially harmful.
... grains help your body make energy from food. Vitamins Hang Out in Water and Fat There are ... acid, B12 (cobalamine), biotin, and pantothenic acid. Continue Vitamins Feed Your Needs Your body is one powerful ...
About 40% of the therapeutic agents in use today exert their effects through seven-transmembrane receptors (7TMRs). When activated by ligands, these receptors trigger two pathways that independently transduce signals to the cell: one through heterotrimeric GTP-binding proteins (G proteins) and one through ?-arrestins; so-called biased agonists can selectively activate these distinct pathways. Here, we investigate selective activation of these pathways through the use of a biased agonist for the type 1 parathyroid hormone (PTH)�PTH-related protein receptor (PTH1R), (D-Trp12, Tyr34)-PTH(7�34) (PTH-?arr), which activates ?-arrestin but not classic G protein signaling. In mice, PTH-?arr induces anabolic bone formation, as does the nonselective agonist PTH (1�34), which activates both mechanisms. In ?-arrestin2�null mice, the increase in bone mineral density evoked by PTH(1�34) is attenuated and that stimulated by PTH-?arr is ablated. The ?-arrestin2�dependent pathway contributes primarily to trabecular bone formation and does not stimulate bone resorption. These results show that a biased agonist selective for the ?-arrestin pathway can elicit a response in vivo distinct from that elicited by nonselective agonists. Ligands with these properties may form the basis for improved 7TMR-directed pharmacologic agents with enhanced therapeutic specificity. PMID:20368153
Gesty-Palmer, Diane; Flannery, Pat; Yuan, Ling; Corsino, Leonor; Spurney, Robert; Lefkowitz, Robert J.; Luttrell, Louis M.
Epithelial-to-mesenchymal transition (EMT) has been shown to play an important role in renal fibrogenesis. Recent studies suggested parathyroid hormone (PTH) could accelerate EMT and subsequent organ fibrosis. However, the precise molecular mechanisms underlying PTH-induced EMT remain unknown. The present study was to investigate whether Wnt/?-catenin signaling pathway is involved in PTH-induced EMT in human renal proximal tubular cells (HK-2 cells) and to determine the profile of gene expression associated with PTH-induced EMT. PTH could induce morphological changes and gene expression characteristic of EMT in cultured HK-2 cells. Suppressing ?-catenin expression or DKK1 limited gene expression characteristic of PTH-induced EMT. Based on the PCR array analysis, PTH treatment resulted in the up-regulation of 18 genes and down-regulation of 9 genes compared with the control. The results were further supported by a western blot analysis, which showed the increased Wnt4 protein expression. Wnt4 overexpression also promotes PTH-induced EMT in HK-2 cells. The findings demonstrated that PTH-induced EMT in HK-2 cells is mediated by Wnt/?-catenin signal pathway, and Wnt4 might be a key gene during PTH-induced EMT. PMID:25337242
Guo, Yunshan; Li, Zhen; Ding, Raohai; Li, Hongdong; Zhang, Lei; Yuan, Weijie; Wang, Yanxia
Wilms' tumour (WT) has a diverse and complex molecular aetiology, with several different loci identified by cytogenetic and molecular analyses. One such locus is on chromosome 7p, where cytogenetic abnormalities and loss of heterozygosity (LOH) indicate the presence of a Wilms' tumour suppressor gene. In order to isolate a candidate gene for this locus, we have characterized the breakpoint regions at a novel constitutional chromosome translocation (t(1;7)(q42;p15)), found in a child with WT and skeletal abnormalities. We identified two genes that were interrupted by the translocation: the parathyroid hormone-responsive B1 gene (PTH-B1) at 7p and obscurin at 1q. With no evidence for LOH at 1q42, we focused on the characterization of PTH-B1. We detected novel alternately spliced isoforms of PTH-B1, which were expressed in a wide range of adult and foetal tissues. Importantly, expression of two isoforms were disrupted in the WT of the t(1;7) patient. We also identified an additional splice isoform expressed only in 7p LOH tumours. The disruption of PTH-B1 by the t(1;7), together with aberrant splicing in sporadic WTs, suggests that PTH-B1 is a candidate for the 7p Wilms' tumour suppressor gene. PMID:12618763
Vernon, Ellen G; Malik, Karim; Reynolds, Paul; Powlesland, Rachel; Dallosso, Anthony R; Jackson, Sally; Henthorn, Karla; Green, Eric D; Brown, Keith W
AIMS--To determine the expression of parathyroid hormone related protein (PTHrP) and interleukin-6 (IL-6) mRNAs and their possible relation in malignant tumours, derived from patients with and without hypercalcaemia, commonly associated with humoral hypercalcaemia of malignancy. METHODS--PTHrP and IL-6 mRNA expression was studied by northern blot analysis in tumour specimens from 13 consecutive patients. Six patients (two with hypercalcaemia) had squamous cell carcinomas of the larynx and seven (one with hypercalcaemia) had renal cell carcinomas. RESULTS--There was no relation between the histological features of the tumours and the expression of either PTHrP or IL-6 mRNAs. PTHrP mRNA was detected in all squamous cell carcinomas, expression being highest in the two patients with hypercalcaemia. In the renal cell carcinomas PTHrP mRNA was expressed only in the patient with hypercalcaemia. IL-6 mRNA was detected in nearly all tumours studied but there was no apparent relation between its expression and that of PTHrP mRNA or serum calcium concentrations. CONCLUSIONS--PTHrP mRNA expression is increased in patients with hypercalcaemia but is not related to IL-6 mRNA expression. The results suggest a quantitative relation between PTHrP gene expression and hypercalcaemia, and imply that different mechanisms account for this expression in squamous and renal cell carcinomas. Images PMID:8537484
Schweitzer, D H; Boxman, I L; L�wik, C W; van Krieken, J H; Weissglas, M G; Baatenburg de Jong, R J; Papapoulos, S E
In 50-90% of cases, humoral hypercalcemia of malignancy (HHM) is due to tumor secretion of parathyroid hormone-related protein (PTHrP). Glucocorticoids are sometimes used as calcium lowering agents and there are in vitro results showing that glucocorticoids diminish PTHrP production. In this study we tested whether the serum-calcium-lowering effect of glucocorticoids is due to decreased PTHrP production by the tumor. As an animal and cell culture model we used the Walker carcinosarcoma (WCS) 256, a rat mammary carcinoma cell line producing PTHrP. In vitro, dexamethasone caused a dose-dependent inhibition of PTHrP production, whereby already 1-5 nmol/L revealed a significant decrease by WCS 256 cells. In contrast to these in vitro results, in WCS 256 tumor-bearing rats, dexamethasone (4 mg/kg body weight on day 4, and 1 mg/kg body weight from day 5 until day 7 after WCS transplantation; circulating dexamethasone levels > 20 nmol/L) did not decrease PTHrP production, PTHrP secretion, serum calcium, or tumor weight in vivo. We conclude that, in this PTHrP-mediated model of humoral hypercalcemia of malignancy, glucocorticoids do not decrease PTHrP production and secretion in vivo and do not show a calcium-lowering effect. PMID:8726387
Schilling, T; Pecherstorfer, M; Blind, E; Kohl, B; Wagner, H; Ziegler, R; Raue, F
Chitosan (CS) and epoxy propyl trimethyl ammonium chloride (EPTAC) were used to prepare the water-soluble N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC). HTCC and sodium tripolyphosphate (TPP) were mixed to form HTCC nanoparticles based on ionic gelation. Parathyroid hormone-related protein 1-34 (PTHrP1-34) was incorporated into the HTCC nanoparticles. The particle size and morphology of nanoparticles were determined by transmission electron microscopy (TEM). HTCC/PTHrP1-34 nanoparticles were 100-180 nm in size and their encapsulation efficiency and loading capacity were related to HTCC concentration, TPP concentration and initial concentration of PTHrP1-34. Relatively optimum encapsulation efficiency (78.4%) and loading capacity (13.7%) of PTHrP1-34 is achieved, and the in vitro release profile of PTHrP1-34 from nanoparticles has an initial burst, which is followed up by a slow release phase. These studies showed that HTCC/PTHrP1-34 nanoparticles are suitable for the treatment of osteoporosis, because of their slow-continuous-release properties, and the relevant in vivo experiments and clinical trials should be further studied. PMID:20435115
Zhao, Sheng-hao; Wu, Xiao-ting; Guo, Wei-chun; Du, Yu-min; Yu, Ling; Tang, Jin
Autoregulation in the parathyroid glands by PTH\\/PTHrP receptor ligands in normal and uremic rats
Autoregulation in the parathyroid glands by PTH\\/PTHrP receptor ligands in normal and uremic rats.BackgroundThe secretion of parathyroid hormone (PTH) from the parathyroid glands might be regulated by autocrine\\/paracrine factors. We have previously shown that N-terminal parathyroid hormone-related protein (PTHrP) enhanced the secretory PTH response to low calcium in vivo and in vitro in rat parathyroid glands. N-terminal PTHrP fragments are
Ewa Lewin; Bartolome Garfia; Yolanda Almaden; Mariano Rodriguez; Klaus Olgaard
Summary��Urinary excretion of calcium (Ca) was measured in 9 patients with pseudohypoparathyroidism (PHP) type I�3 with Albright's\\u000a hereditary osteodystrophy (AHO): AHO(+) and 6 without AHO: AHO(?)�and in 13 with idiopathic hypoparathyroidism (IHP), treated\\u000a with active vitamin D3 (1,25(OH)2D3 or 1?OHD3) to maintain serum Ca levels at 8.4�9.5 mg\\/dl. Fasting urinary excretion of Ca in PHP was significantly lower than that
Kazutoshi Mizunashi; Yohtaro Furukawa; Hyo Euy Sohn; Ryo Miura; Shigeru Yumita; Kaoru Yoshinaga
Mechanical loading and intermittent parathyroid (iPTH) treatment are both osteoanabolic stimuli, and are regulated by partially overlapping cellular signaling pathways. iPTH has been shown clinically to be effective in increasing bone mass and reducing fracture risk. Likewise, mechanical stimulation can significantly enhance bone apposition and prevent bone loss, but its clinical effects on fracture susceptibility are less certain. Many of the osteogenic effects of iPTH are localized to biomechanically suboptimal bone surfaces, whereas mechanical loading directs new bone formation to high-stress areas and not to strain-neutral areas. These differences in localization in new tissue, resulting from load-induced vs iPTH-induced bone accumulation, should affect the relation between bone mass and bone strength, or �tissue economy.� We investigated the changes in bone mass and strength induced by 6 wks mechanical loading, and compared them to changes induced by 6 wks iPTH treatment. Loading and iPTH both increased ulnar bone accrual, as measured by bone mineral density and content, and fluorochrome-derived bone formation. iPTH induced a significantly greater increase in bone mass than loading, but ulnar bone strength was increased approximately the same amount by both treatments. Mechanical loading during growth can spatially optimize new bone formation to improve structural integrity with a minimal increase in mass, thereby increasing tissue economy i.e., the amount of strength returned per unit bone mass added. Furthermore, exercise studies in which only small changes in bone mass are detected might be more beneficial to bone health and fracture resistance than has commonly been presumed. PMID:20306026
McAteer, Maureen E.; Niziolek, Paul J.; Ellis, Shana N.; Alge, Daniel L.; Robling, Alexander G.
Tenofovir disoproxil fumarate (TDF) causes bone, endocrine, and renal changes by an unknown mechanism(s). Data are limited on tenofovir pharmacokinetics and these effects. Using baseline data from a multicenter study of HIV-infected youth on stable treatment with regimens containing TDF (n = 118) or lacking TDF (n = 85), we measured cross-sectional associations of TDF use with markers of renal function, vitamin D-calcium-parathyroid hormone balance, phosphate metabolism (tubular reabsorption of phosphate and fibroblast growth factor 23 [FGF23]), and bone turnover. Pharmacokinetic-pharmacodynamic associations with plasma tenofovir and intracellular tenofovir diphosphate concentrations were explored among those receiving TDF. The mean age was 20.9 (standard deviation [SD], 2.0) years; 63% were male; and 52% were African American. Compared to the no-TDF group, the TDF group showed lower mean estimated glomerular filtration rates and tubular reabsorption of phosphate, as well as higher parathyroid hormone and 1,25-dihydroxy vitamin D [1,25-OH(2)D] levels. The highest quintile of plasma tenofovir concentrations was associated with higher vitamin D binding protein, lower free 1,25-OH(2)D, higher 25-OH vitamin D, and higher serum calcium. The highest quintile of intracellular tenofovir diphosphate concentration was associated with lower FGF23. Higher plasma tenofovir concentrations were associated with higher vitamin D binding protein and lower free 1,25-OH(2)D, suggesting a functional vitamin D deficiency explaining TDF-associated increased parathyroid hormone. The finding of lower FGF23 accompanying higher intracellular tenofovir diphosphate suggests that different mechanisms mediate TDF-associated changes in phosphate handling. Separate pharmacokinetic properties may be associated with distinct TDF toxicities: tenofovir with parathyroid hormone and altered calcium balance and tenofovir diphosphate with hypophosphatemia and FGF23 regulation. (The clinical trial registration number for this study is NCT00490412 and is available online at http://clinicaltrials.gov/ct2/show/NCT00490412.) PMID:24002093
Kiser, Jennifer J.; Stephensen, Charles B.; Hazra, Rohan; Flynn, Patricia M.; Wilson, Craig M.; Rutledge, Brandy; Bethel, James; Pan, Cynthia G.; Woodhouse, Leslie R.; Van Loan, Marta D.; Liu, Nancy; Lujan-Zilbermann, Jorge; Baker, Alyne; Kapogiannis, Bill G.; Gordon, Catherine M.
MINERAL ADDITIVES, HORMONE IMPLANTS, AND VITAMIN A INJECTIONS AS RELATED TO URINARY CALCULI FORMATION XN FATTENING STEER CALVES FED MOIST SORGHUM HEADS A Thesis By WILLIAM S. MCGINNIS Submitted to the Graduate College of the Texas A 8a...M University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE January 1967 Major Subject: Animal Science MINERAL ADDITIVES, HORMONE IMPLANTS, AND VITAMIN A INJECTIONS AS RELATED TO URINARY CALCULI FORMATION IN FATTENING...
McGinnis, William Sams
Chemotherapy-induced alopecia is a major source of psychological stress in patients undergoing cancer chemotherapy, and it can influence treatment decisions. Although there is currently no therapy for alopecia, a fusion protein of parathyroid hormone and collagen binding domain (PTH-CBD) has shown promise in animal models. The aim of this study was to determine whether there are dose-dependent effects of PTH-CBD on chemotherapy-induced alopecia in a mouse model. C57BL/6J mice were waxed to synchronize hair follicles; treated on day 7 with vehicle or PTH-CBD (100, 320, and 1000 mcg/kg subcutaneous injection); and treated on day 9 with vehicle or cyclophosphamide (150 mg/kg intraperitoneally). Mice were photographed every 3-4 days and killed on day 63 for histological analysis. Photographs were quantified by gray scale analysis to assess hair content. Mice not receiving chemotherapy showed regrowth of hair 2 weeks after waxing and normal histology after 2 months. Mice receiving chemotherapy alone showed marked hair loss after chemotherapy, which was sustained for 10 days and was followed by rapid regrowth of a normal coat. Histological analysis revealed rapid cycling dystrophic anagen/catagen follicles. Animals receiving chemotherapy and PTH-CBD showed decreased hair loss and more rapid regrowth of hair than that seen with chemotherapy alone (increased hair growth by gray scale analysis, P<0.05), and the effects were dose dependent. Histologically, hair follicles in animals receiving the highest dose of PTH-CBD were in a quiescent phase, similar to that in mice that did not receive chemotherapy. Single-dose subcutaneous administration of PTH-CBD showed dose-dependent effects in minimizing hair loss and speeding up recovery from chemotherapy-induced alopecia. PMID:24710191
Katikaneni, Ranjitha; Ponnapakkam, Tulasi; Seymour, Andrew; Sakon, Joshua; Gensure, Robert
Context Velcalcetide, also known as AMG 416, is a novel, long-acting selective peptide agonist of the calcium sensing receptor. It is being developed as an intravenous treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients with chronic kidney disease�mineral and bone disorder. Objective To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of velcalcetide in healthy male volunteers. Methods The study was a double-blind, randomized, placebo-controlled, single-dose, dose-escalation study in healthy males aged 18�45 years conducted at a single center. Each cohort included eight subjects randomized 6:2 to velcalcetide or placebo. Intervention Velcalcetide at 0.5, 2, 5 and 10 mg or placebo was administered intravenously. Outcomes Measurements included plasma ionized calcium (iCa), serum total calcium, intact parathyroid hormone (iPTH), phosphorus and fibroblast growth factor-23 (FGF23), 1,25-dihydroxyvitamin D, calcitonin and urine creatinine, calcium and phosphorus and plasma pharmacokinetics for velcalcetide. Vital signs, safety biochemical and hematological indices, and adverse events were monitored throughout the study. Results Intravenous administration of velcalcetide was well tolerated with no adverse reaction of nausea, vomiting or diarrhea reported. Velcalcetide mediated dose-dependent decreases in serum iPTH at 30 min, FGF23 at 24 h and iCa at 12 h post dose (P < 0.05) and in urine fractional excretion of phosphorus and increases in tubular reabsorption of phosphorus. Velcalcetide plasma exposure increased in a dose-related manner and the terminal elimination of half-life was comparable across the dose range evaluated and ranged from 18.4 to 20.0 h. Conclusion Single IV doses of velcalcetide were well tolerated and associated with rapid, sustained, dose-dependent reductions in serum PTH. The results support further evaluation of velcalcetide as a treatment for SHPT in hemodialysis patients. PMID:24235081
Martin, Kevin J.; Bell, Gregory; Pickthorn, Karen; Huang, Saling; Vick, Andrew; Hodsman, Peter; Peacock, Munro
The structures of C- and N-terminally monoPEGylated human parathyroid hormone fragment hPTH(1-34) as well as their unmodified counterparts, poly(ethylene glycol) (PEG) and hPTH(1-34), have been studied by small-angle neutron scattering (SANS). The scattering results show that free hPTH(1-34) in 100 mM phosphate buffer (pH 7.4) aggregates into clusters. After conjugation with PEG, the PEG-peptide conjugates self-assemble into a supramolecular core-shell structure with a cylindrical shape. The PEG chains form a shell around the hPTH(1-34) core to shield hPTH(1-34) from the solvent. The detailed structural information on the self-assembled structures is extracted from SANS using a model of the cylindrical core with a shell of Gaussian chains attached to the core surface. On the basis of the data, because of the charge-dipole interactions between the conjugated PEG chain and the peptide, the conjugated PEG chain forms a more collapsed conformation compared to free PEG. Moreover, the size of the self-assembled structures formed by the C-terminally monoPEGylated hPTH(1-34) is about 3 times larger than that of the N-terminally monoPEGylated hPTH(1-34). The different aggregation numbers of the self-assembled structures, triggered by different PEGylation sites, are reported. These size discrepancies because of different PEGylation sites could potentially affect the pharmacokinetics of the hPTH(1-34) drug. PMID:25168862
Liu, Chih-Ying; Li, Xin; Chen, Wen-Yih; Chang, Li-Chiao; Chen, Yi-Fan; Chen, Hsin-Lung; Sun, Ya-Sen; Lai, Hsiu-Yun; Huang, E-Wen
Parathyroid hormone (PTH) regulates the transcription of many genes involved in bone remodeling in osteoblasts. One of these genes is matrix metalloproteinase-13 (MMP-13), which is involved in bone remodeling and early stages of endochondral bone formation. We have previously shown that Mmp-13 gene expression is highly induced by PTH treatment in osteoblastic UMR 106-01 cells, as well as primary osteoblasts. Here, we show that p300/CBP-associated factor (PCAF), in addition to p300 and Runx2, is required for PTH activation of Mmp-13 transcription. PCAF was increasingly recruited to the MMP-13 proximal promoter region after PTH treatment, and this was associated with an increase in RNA polymerase II recruitment and histone acetylation. In addition, PTH treatment increased the acetylation of PCAF, a process that required p300. Knockdown of PCAF, p300, or Runx2 by siRNA decreased Mmp-13 mRNA expression after PTH treatment in both UMR 106-01 cells and primary osteoblasts. We found that there is a mutual dependence between p300 and PCAF to be recruited to the Mmp-13 promoter after PTH treatment. In promoter-reporter assays, p300 and PCAF had an additive effect on PTH stimulation of MMP-13 promoter activity, and this required their histone acetyltransferase activity. Our findings demonstrate that PCAF acts downstream of PTH signaling as a transcriptional coactivator that is required for PTH stimulation of MMP-13 transcription. PCAF cooperates with p300 and Runx2 to mediate PTH activation of MMP-13 transcription. PMID:20870727
Lee, Minnkyong; Partridge, Nicola C.
Prostate cancer bone metastases are unique in that that majority of them induce excessive mineralized bone matrix, through undefined mechanisms, as opposed to most other cancers that induce bone resorption. Parathyroid hormone-related protein (PTHrP) is produced by prostate cancer cells and intermittent PTHrP exposure has bone anabolic effects suggesting PTHrP could contribute to the excess bone mineralization. Wnts are bone productive factors produced by prostate cancer cells and the Wnt inhibitor DKK1 has been shown to promote prostate cancer progression. These findings, in conjunction with the observation that PTHrP expression increases and DKK1 expression decreases as prostate cancer progresses led to the hypothesis that PTHrP could be a negative regulator of DKK1 expression in prostate cancer cells, and hence allow the osteoblastic activity of Wnts to be realized. To test this, we first demonstrated that PTHrP downregulated DKK1 mRNA and protein expression. We then found through multiple mutated DKK1 promoter assays that PTHrP, through c-Jun activation, downregulated the DKK1 promoter through a TCF-response element site. Furthermore, chromatin immunoprecipitation (ChIP) and reChIP assays revealed that PTHrP-mediated this effect through inducing c-Jun to bind to a transcriptional activator complex consisting of ?-catenin that binds the most proximal DKK1 promoter TCF-response element. Together, these results demonstrate a novel signaling linkage between PTHrP and Wnt signaling pathways that results in downregulation of a Wnt inhibitor allowing for Wnt activity that could contribute the osteoblastic nature of prostate cancer. PMID:23752183
Zhang, H.; Yu, C.; Dai, J.; Keller, JM.; Hua, A.; Sottnik, JL.; Shelley, G.; Hall, CL.; Park, SI.; Yao, Z.; Zhang, J.; McCauley, LK.; Keller, ET.
The Walker carcinosarcoma (WCS) 256 is a well-characterized rat model of humoral hypercalcemia of malignancy (HHM). We addressed the question of whether parathyroid hormone-related protein (PTHrP) is the factor responsible for mediating HHM in this model. WCS 256 cells were subcutaneously implanted in female rats. We examined the plasma at days 0, 2, 4, 6, and 8. The midregional PTHrP measured by radioimmunoassay (RIA) and the plasma calcium increased significantly. Measuring PTHrP by a two-site immunoradiometric assay (IRMA) showed comparable results. There was a strong positive correlation between plasma calcium and midregional PTHrP (r = 0.85, p < 0.0001). A strong positive correlation between tumor weight and both midregional PTHrP (r = 0.83, p < 0.0001) and plasma calcium (r = 0.87, p < 0.0001) was also found. After surgical removal of the tumor at day 5, both plasma calcium and plasma PTHrP levels fell to within the normal range. Ip administration of native polyclonal antiserum against PTHrP(53-84) led to a significant decrease of plasma calcium. Extracted WCS 256 tumor showed 5-fold increased levels of midregional PTHrP compared with liver. Immunohistochemistry and Western blot were positive for PTHrP. RNA from the WCS 256 tumor was positive for PTHrP whereas liver tissue RNA was negative. WCS 256 cells grown in vitro also secreted PTHrP into the medium. We conclude that PTHrP is synthesized and secreted by WCS 256 and that PTHrP is the factor responsible for mediating hypercalcemia in the WCS 256 rat model. PMID:7747633
Schilling, T; Blind, E; Baier, R; Sinn, H P; Moallem, E; Silver, J; Ziegler, R; Raue, F
Parathyroid hormone-related protein (PTHrP) is expressed by human prostatic tissues and cancer cell lines. PTHrP enhances tumor cell growth and metastasis in vivo and upregulates pro-invasive integrin ?6?4 expression in vitro. Hallmarks of malignant tumor cells include resistance to apoptosis and anchorage-independent cell growth. In this study, we used the human prostate cancer cell lines C4-2 and PC-3 as model systems to study the effects of PTHrP on these processes. We report that PTHrP protects these cells from doxorubicin-induced apoptosis and promotes anchorage-independent cell growth via an intracrine pathway. Conversely, autocrine/paracrine PTHrP action increases apoptosis in C4-2 cells and has no effect on apoptosis in PC-3 cells. The intracrine effects of PTHrP on apoptosis are mediated via activation of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway. PTHrP also affects the phosphorylation state of Akt substrates implicated in apoptosis suppression, including glycogen synthase kinase-3 and Bad. The pro-survival effects of PTHrP are accompanied by increases in the ratio of anti- to pro-apoptosis members of the Bcl-2 family and in levels of c-myc. PTHrP also increases NF-?B activity via a PI3-K-dependent pathway. Integrin ?6?4 is known to activate PI3-K. Here we also show that knockdown of integrin ?6?4 negates the PTHrP-mediated activation of the PI3-K/Akt pathway. Taken together, these observations provide evidence of a link between PTHrP and the PI3-K/Akt signaling pathway through integrin ?6?4, resulting in the activation of survival pathways. Targeting PTHrP production in prostate cancer may thus prove therapeutically beneficial. PMID:19584267
Bhatia, Vandanajay; Mula, Ramanjaneya V.; Weigel, Nancy L.; Falzon, Miriam
The mechanisms whereby the parathyroid hormone (PTH) exerts its anabolic action on bone are incompletely understood. We previously showed that inhibition of ERK1/2 enhanced Smad3-induced bone anabolic action in osteoblasts. These findings suggested the hypothesis that changes in gene expression associated with the altered Smad3-induced signaling brought about by an ERK1/2 inhibitor would identify novel bone anabolic factors in osteoblasts. We therefore performed a comparative DNA microarray analysis between empty vector-transfected mouse osteoblastic MC3T3-E1 cells and PD98059-treated stable Smad3-overexpressing MC3T3-E1 cells. Among the novel factors, Tmem119 was selected on the basis of its rapid induction by PTH independent of later increases in endogenous TGF-?. The levels of Tmem119 increased with time in cultures of MC3T3-E1 cells and mouse mesenchymal ST-2 cells committed to the osteoblast lineage by BMP-2. PTH stimulated Tmem119 levels within 1 h as determined by Western blot analysis and immunocytochemistry in MC3T3-E1 cells. MC3T3-E1 cells stably overexpressing Tmem119 exhibited elevated levels of Runx2, osteocalcin, alkaline phosphatase, and ?-catenin, whereas Tmem119 augmented BMP-2-induced Runx2 levels in mesenchymal cells. Tmem119 interacted with Runx2, Smad1, and Smad5 in C2C12 cells. In conclusion, we identified a Smad3-related factor, Tmem119, that is induced by PTH and promotes differentiation in mouse osteoblastic cells. Tmem119 is an important molecule in the pathway downstream of PTH and Smad3 signaling in osteoblasts. PMID:21239498
Hisa, Itoko; Inoue, Yoshifumi; Hendy, Geoffrey N.; Canaff, Lucie; Kitazawa, Riko; Kitazawa, Sohei; Komori, Toshihisa; Sugimoto, Toshitsugu; Seino, Susumu; Kaji, Hiroshi
Alopecia is a psychologically devastating complication of chemotherapy for which there is currently no effective therapy. PTH-CBD is a collagen-targeted parathyroid hormone analog that has shown promise as a therapy for alopecia disorders. This study compared the efficacy of prophylactic versus therapeutic administration of PTH-CBD in chemotherapy-induced alopecia using a mouse model that mimics the cyclic chemotherapy dosing used clinically. C57BL/6J mice were treated with a single subcutaneous injection of PTH-CBD (320 mcg/kg) or vehicle control before or after hair loss developing from three courses of cyclophosphamide chemotherapy (50-150 mg/kg/week). Mice receiving chemotherapy alone developed hair loss and depigmentation over 6-12 months. Mice pretreated with PTH-CBD did not develop these changes and maintained a normal-appearing coat. Mice treated with PTH-CBD after development of hair loss showed a partial recovery. Observations of hair loss were confirmed quantitatively by gray scale analysis. Histological examination showed that in mice receiving chemotherapy alone, there were small, dystrophic hair follicles mostly in the catagen phase. Mice receiving PTH-CBD before chemotherapy showed a mix of normal-appearing telogen and anagen hair follicles with no evidence of dystrophy. Mice receiving PTH-CBD therapy after chemotherapy showed intermediate histological features. PTH-CBD was effective in both the prevention and the treatment of chemotherapy-induced alopecia in mice, but pretreatment appears to result in a better cosmetic outcome. PTH-CBD shows promise as an agent in the prevention of this complication of chemotherapy and improving the quality of life for cancer patients. PMID:24025564
Katikaneni, Ranjitha; Ponnapakkam, Tulasi; Matsushita, Osamu; Sakon, Joshua; Gensure, Robert
This study investigates the time-dependent effects of cinacalcet on serum calcium, phosphorus, and parathyroid hormone (PTH) levels in 5/6 nephrectomized (NX) rats with experimental chronic renal insufficiency. In this study, 5/6 NX male, Sprague�Dawley rats were treated with vehicle or cinacalcet (10 mg/kg, oral, 1� daily). On Day 0 (before treatment), Day 12 and 13 after treatment (to approximate the clinical practice), and also at 0, 1, 4, 8, 16, and 24 hours after the last dosing, blood was collected for analysis. After 12 or 13 days of cinacalcet treatment, modest changes were observed in serum Ca and phosphorus (Pi), while PTH decreased by >45% to Sham levels (152 � 15 pg/mL). Detailed mapping found that cinacalcet caused a significant time-dependent decrease in serum Ca following dosing, reaching a lowest point at 8 hours (decrease by 20% to 8.43 � 0.37 mg/dL), and then returning to normal at 24 hours. Cinacalcet also caused a significant increase in serum Pi levels (by 18%). To investigate the potential mechanism of action, a broad approach was taken by testing cinacalcet in a panel of 77 protein-binding assays. Cinacalcet interacted with several channels, transporters, and neurotransmitter receptors, some of which are involved in brain and heart, and may impact Ca homeostasis. Cinacalcet dose-dependently increased brain natriuretic peptide (BNP) mRNA expression by 48% in cardiomyocytes, but had no significant effects on left ventricular hypertrophy and cardiac function. The results suggest that cinacalcet's hypocalcemic effect may be due to its nonspecific interaction with other receptors in brain and heart. PMID:24303131
Wu-Wong, J Ruth; Nakane, Masaki; Chen, Yung-wu; Mizobuchi, Masahide
NASA Technical Reports Server (NTRS)
Osteoblasts respond to both fluid shear and parathyroid hormone (PTH) with a rapid increase in intracellular calcium concentration ([Ca2+]i). Because both stimuli modulate the kinetics of the mechanosensitive cation channel (MSCC), we postulated PTH would enhance the [Ca2+]i response to fluid shear by increasing the sensitivity of MSCCs. After a 3-minute preflow at 1 dyne/cm2, MC3T3-E1 cells were subjected to various levels of shear and changes in [Ca2+]i were assessed using Fura-2. Pretreatment with 50 nM bovine PTH(1-34) [bPTH(1-34)] significantly enhanced the shear magnitude-dependent increase in [Ca2+]i. Gadolinium (Gd3+), an MSCC blocker, significantly inhibited the mean peak [Ca2+]i response to shear and shear + bPTH(1-34). Nifedipine (Nif), an L-type voltage-sensitive Ca2+ channel (VSCC) blocker, also significantly reduced the [Ca2+]i response to shear + bPTH(1-34), but not to shear alone, suggesting VSCC activation plays an interactive role in the action of these stimuli together. Activation of either the protein kinase C (PKC) or protein kinase A (PKA) pathways with specific agonists indicated that PKC activation did not alter the Ca2+ response to shear, whereas PKA activation significantly increased the [Ca2+]i response to lower magnitudes of shear. bPTH(1-34), which activates both pathways, induced the greatest [Ca2+]i response at each level of shear, suggesting an interaction of these pathways in this response. These data indicate that PTH significantly enhances the [Ca2+]i response to shear primarily via PKA modulation of the MSCC and VSCC.
Ryder, K. D.; Duncan, R. L.
The signal transducer and activator of transcription 5a (Stat5a) modulates genes involved in proliferation and survival and plays pivotal roles in regulating the function of the mammary gland during pregnancy, lactation, and involution. However, there is little information about the effects of Stat5a on apoptosis of goat mammary gland epithelial cells (GMECs). In addition, parathyroid hormone-related protein (PTHrP) is a key regulator in cellular calcium transport, mammary gland development and breast tumor biology. This study aimed to explore the interaction of Stat5a and PTHrP in GMEC apoptosis. Quantitative real time PCR (qRT-PCR) suggested that Stat5a was predominantly expressed in the mammary gland, lung, liver and spleen of goats. Treating the GMECs with pimozide, an inhibitor of Stat5a that decreases Stat5a tyrosine phosphorylation, increased PTHrP levels in GMECs in a dose-dependent manner and simultaneously promoted apoptosis of the GMECs. We also demonstrated that PTHrP inhibition induced GMEC apoptosis and restrained cell proliferation. In contrast, PTHrP overexpression protected GMECs from pimozide- and calcium-induced apoptosis, and promoted cell proliferation. Furthermore, pimozide and CaCl2 downregulated the antiapoptotic protein Bcl-2 mRNA expression, respectively, and these effects were protected by PTHrP overexpression. Interestingly, we also found that Stat5a suppressed the expression of matrix metalloproteinase 9 (MMP-9) which can induce goat mammary epithelial cell migration, but PTHrP increased MMP-9 mRNA level. Thus, Stat5a may regulate GMEC survival by regulating the expression of PTHrP. PMID:25194899
Li, Hui; Zheng, Huiling; Sun, Yongsen; Yu, Qian; Li, Lihui
Vitamin D deficiency leads to secondary hyperparathyroidism, in- creased bone turnover, and bone loss and, when severe, to osteoma- lacia. Vitamin D deficiency is common in elderly people, especially the institutionalized. The definition of vitamin D deficiency is hampered by the fact that large interlaboratory differences exist in assays for serum 25-hydroxyvitamin D (25OHD), the main circulating metab- olite. The
Lung Cancer and Hormone Replacement Therapy: Association in the Vitamins and Lifestyle Study
Purpose Lung cancer is the leading cause of cancer-related mortality among women. The role of hormone replacement therapy (HRT) in lung cancer development is unclear. Patients and Methods We evaluated a prospective cohort of 36,588 peri- and postmenopausal women aged 50 to 76 years from Washington State recruited in 2000 to 2002 (Vitamins and Lifestyle [VITAL] Study). Lung cancer cases (n = 344) were identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry during 6 years of follow-up. Hazard ratios (HRs) associated with use and duration of specific HRT formulations were calculated for total incident lung cancer, specific morphologies, and cancer by stage at diagnosis. Results After adjusting for smoking, age, and other potential confounders, there was an increased risk of incident lung cancer associated with increasing duration of estrogen plus progestin (E+P) use (HR = 1.27 for E+P use 1 to 9 years, 95% CI, 0.91 to 1.78; and HR = 1.48 for E+P use ? 10 years, 95% CI, 1.03 to 2.12; P for trend = .03). There was no association with duration of unopposed estrogen use. Duration of E+P use was associated with an advanced stage at diagnosis (P for trend = .03). Conclusion Use of E+P increased the risk of incident lung cancer in a duration-dependent manner, with an approximate 50% increased risk for use of 10 years or longer. These findings may be helpful for informing women of their risk of developing lung cancer and delineating important pathways involved in hormone metabolism and lung cancer. PMID:20159813
Slatore, Christopher G.; Chien, Jason W.; Au, David H.; Satia, Jessie A.; White, Emily
Vitamin D, the major steroid hormone that controls mineral ion homeostasis, exerts its actions through the vitamin D receptor (VDR). The VDR is expressed in many tissues, including several tissues not thought to play a role in mineral metabolism. Studies in kindreds with VDR mutations (vitamin D-dependent rickets type II, VDDR II) have demonstrated hypocalcemia, hyperparathyroidism, rickets, and osteomalacia. Alopecia, which is not a feature of vitamin D deficiency, is seen in some kindreds. We have generated a mouse model of VDDR II by targeted ablation of the second zinc finger of the VDR DNA-binding domain. Despite known expression of the VDR in fetal life, homozygous mice are phenotypically normal at birth and demonstrate normal survival at least until 6 months. They become hypocalcemic at 21 days of age, at which time their parathyroid hormone (PTH) levels begin to rise. Hyperparathyroidism is accompanied by an increase in the size of the parathyroid gland as well as an increase in PTH mRNA levels. Rickets and osteomalacia are seen by day 35; however, as early as day 15, there is an expansion in the zone of hypertrophic chondrocytes in the growth plate. In contrast to animals made vitamin D deficient by dietary means, and like some patients with VDDR II, these mice develop progressive alopecia from the age of 4 weeks. PMID:9275211
Li, Yan Chun; Pirro, Alison E.; Amling, Michael; Delling, Gunter; Baron, Roland; Bronson, Roderick; Demay, Marie B.
In residential care, inadequate calcium and folate intakes and low serum vitamin D (25(OH)D) concentrations are common. We assessed whether daily provision of calcium, folate, and vitamin D3�fortified milk for 6 months improved nutritional status (serum micronutrients), bone quality (heel ultrasound), bone turnover markers (parathyroid hormone, C-terminal collagen I telopeptide, terminal propeptide of type I procollagen), and\\/or muscle strength and
Jessica A. Grieger; Caryl A. Nowson
In previous studies, we have shown that steroid hormone resistance in New World primates occurs in the absence of abnormal expression of cognate nuclear receptors. Rather, these animals have elevated levels of heterogeneous nuclear ribonucleoproteins (hnRNPs) that act as hormone response element-binding proteins and attenuate target gene transactivation. Here we present evidence for a similar mechanism in humans via a patient with resistance to the active form of vitamin D [1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3))] who presented with normal vitamin D receptor (VDR) expression. Initial cotransfection studies showed that the cells of the patient suppressed basal and hormone-induced transactivation by wild-type VDR. Electrophoretic mobility-shift assays and Western/Southwestern blot analyses indicated that this suppressive effect was due to overexpression of a nuclear protein that specifically interacts with a DNA response element known to bind retinoid X receptor-VDR heterodimers. Ab blocking in electrophoretic mobility-shift assays indicated that this dominant-negative acting protein was in the hnRNPA family of nucleic acid-binding proteins. Further studies have shown that several members of this family, most notably hnRNPA1, were able to suppress basal and 1,25(OH)(2)D(3)-induced luciferase activity. We therefore propose that this case of vitamin D resistance in a human subject is similar to that previously described for New World primates in which abnormal expression of a hormone response element-binding protein can cause target cell resistance to 1,25(OH)(2)D(3). That this protein is a member of the hnRNP family capable of interacting with double-stranded DNA highlights a potentially important new component of the complex machinery required for steroid hormone signal transduction. PMID:12716975
Chen, Hong; Hewison, Martin; Hu, Bing; Adams, John S
Context: Obesity is associated with lower serum concentrations of 25-hydroxyvitamin D (25OHD) and higher intact PTH. The threshold of 25OHD needed to maximally suppress intact PTH has been suggested as a marker of optimal vitamin D status. Objective: In this study, we hypothesized that whereas the obese have a higher serum PTH and lower 25OHD, suppression of serum PTH by 25OHD would be independent of body weight. Design, Setting, and Participants: We performed a retrospective analysis on 383 women (ages 24�75 y) with a wide range of body weights (43�185 kg) who were stabilized to 1�1.2 g calcium/d for 1 month before blood draw. Body composition, serum PTH, 25OHD, calcium, and creatinine were measured. Locally weighted regression and smoothing scatterplots were used to depict the association between serum PTH and 25OHD. A nonlinear exponential model determined the point for near maximal suppression of PTH by 25OHD. Results: The point for near maximal suppression of PTH by 25OHD for all women (body mass index, 31.4 � 7.7 kg/m2) occurred at a 25OHD concentration of 21.7 ng/mL (95% confidence interval, 28�48 ng/mL). No point of maximal suppression was found for nonobese women, yet in the obese women (n = 207; body mass index, >30 kg/m2) suppression of PTH occurred at a 25OHD concentration of 11.1 ng/mL (95% confidence interval, 4.7�17.5 ng/mL). Conclusions: These results suggest that if PTH is suppressed at a lower serum 25OHD in the obese compared to the entire population, the lower average 25OHD concentrations in the obese may not have the same physiological significance as in the general population. PMID:23509103
Lee, Esther J.; Sukumar, Deeptha; Durazo-Arvizu, Ramon; Schneider, Stephen H.
Interleukin-6 production and secretion by human parathyroids
Parathyroid hormone (PTH) stimulates osteoblasts to produce the proinflammatory cytokine interleukin-6 (IL-6), causing bone resorption. In patients with primary hyperparathyroidism, elevated serum levels of IL-6 normalize after resection of parathyroid tumours. Because IL-6 is also expressed in normal parathyroids and in other endocrine cells (adrenal and islet), we hypothesized that parathyroid tumours might contribute directly to the elevated serum IL-6 levels in patients with hyperparathyroidism. Immunohistochemistry identified IL-6, PTH, and chromogranin-A (an endocrine and neuroendocrine tumour marker) in normal, adenomatous and hyperplastic parathyroids. Using immunofluorescence and confocal microscopy, IL-6 co-localized with PTH and with chromogranin-A in parathyroid cells. All cultured parathyroid tumours secreted IL-6 at levels markedly higher than optimally stimulated peripheral blood mononuclear cells. Supernates from cultured parathyroids stimulated proliferation of an IL-6-dependent cell line, and anti-IL-6 MoAb abolished this stimulatory effect. IL-6 mRNA was documented in cultured parathyroid tumours, cultured normal parathyroids, fresh operative parathyroid tumours and fresh operative normal specimens. In conclusion, these data show that parathyroid tumours and normal parathyroids contain, produce and secrete IL-6. Our findings present a novel pathway by which human parathyroids may contribute markedly to IL-6 production and elevation of serum IL-6 levels in patients with hyperparathyroidism. The physiological relevance of IL-6 production by human parathyroids remains to be determined, but IL-6 secretion by parathyroid tumours may contribute to bone loss and to other multi-system complaints observed in these patients. PMID:15030526
Hyperfunctioning cystic parathyroid glands: CT and sonographic findings
Four functioning cystic parathyroid glands were evaluated with computed tomography (CT) and sonography in four patients, only one of whom had prior surgery. Sonography demonstrated solid lesions of decreased echogenicity with fluid-filled cavities near the lower thyroid poles or in the posterosuperior mediastinum. On CT the cystic parts of the lesions were of low attenuation (1-44 H), often with a well defined wall that was better demonstrated after intravenous contrast administration. Fine-needle aspiration biopsy of two of the cystic parathyroids revealed elevated parathyroid hormone levels. These lesions probably represent degenerating adenomas rather than true parathyroid cysts. While the CT and sonographic findings are nonspecific, the diagnosis of a cystic parathyroid should be entertained when a fluid-filled lesion is encountered in the neck of a patient with or without hypercalcemia. The diagnosis may be confirmed by assay of parathyroid hormone from the fluid aspirate.
Krudy, A.G. (National Inst. of Health, Bethesda, MD); Doppman, J.L.; Shawker, T.H.; Spiegel, A.M.; Marx, S.J.; Norton, J.; Schaaf, M.; Moss, M.L.; Weiss, M.A.; Schachner, S.H.
Parathyroid hormone-related peptide (PTHrP) and the parathyroid hormone-PTHrP receptor increase chondrocyte proliferation and delay chondrocyte maturation in endochondral bone development at least partly through cyclic AMP (cAMP)-dependent signaling pathways. Because data suggest that the ability of cAMP to stimulate cell proliferation involves the mitogen-activated protein kinase kinase kinase B-Raf, we hypothesized that B-Raf might mediate the proliferative action of PTHrP in chondrocytes. Though B-Raf is expressed in proliferative chondrocytes, its conditional removal from cartilage did not affect chondrocyte proliferation and maturation or PTHrP-induced chondrocyte proliferation and PTHrP-delayed maturation. Similar results were obtained by conditionally removing B-Raf from osteoblasts. Because A-raf and B-raf are expressed similarly in cartilage, we speculated that they may fulfill redundant functions in this tissue. Surprisingly, mice with chondrocytes deficient in both A-Raf and B-Raf exhibited normal endochondral bone development. Activated extracellular signal-regulated kinase (ERK) was detected primarily in hypertrophic chondrocytes, where C-raf is expressed, and the suppression of ERK activation in these cells by PTHrP or a MEK inhibitor coincided with a delay in chondrocyte maturation. Taken together, these results demonstrate that B-Raf and A-Raf are dispensable for endochondral bone development and they indicate that the main role of ERK in cartilage is to stimulate not cell proliferation, but rather chondrocyte maturation. PMID:17967876
Provot, Sylvain; Nachtrab, Gregory; Paruch, Jennifer; Chen, Adele Pin; Silva, Alcino; Kronenberg, Henry M.
The present studies were designed to examine the consequences of chronic mild elevations of endogenous parathyroid hormone (PTH) in vivo on the PTH receptor-adenylate cyclase system of canine kidney cortex. Hyperparathyroidism was induced in normal dogs by feeding a diet low in calcium, high in phosphorus to the animals for a period of 6-9 wk. This maneuver resulted in a two to threefold increase in the plasma levels of carboxy-terminal immunoreactive PTH. This degree of hyperparathyroidism is similar to that seen in patients with hyperparathyroidism and normal renal function. After 6-9 wk on the diet the animals were killed and basolateral renal cortical membranes prepared for the study of the PTH receptor-adenylate cyclase system in vitro. The dietary hyperparathyroidism resulted in desensitization of the PTH-responsive adenylate cyclase (Vmax 3,648 +/- 654 pmol cyclic (c)AMP/mg protein per 30 min in hyperparathyroid animals vs. 5,303 +/- 348 in normal controls). The Kact (concentration of PTH required for half-maximal enzyme activation) was unchanged. However, PTH receptor binding (125I-norleucyl8-norleucyl18-tyrosinyl34, 125I[Nle8, Nle18, Tyr34] bPTH (1-34) NH2 as radioligand) was not different in the two groups of animals. Thus, dietary hyperparathyroidism resulted in an uncoupling of the PTH receptor-adenylate cyclase system. This defect was not corrected by guanyl nucleotides in vitro, and the effects of guanyl nucleotides on PTH binding and enzyme activation appeared normal. NaF-stimulated enzyme activity was reduced in the hyperparathyroid animals (8,285 +/- 607 pmol cAMP/mg protein per 30 min vs. 10,851 +/- 247 in controls). These data indicate that desensitization of the PTH-responsive adenylate cyclase system of canine kidney as a result of mild chronic elevations of endogenous PTH is due to a postreceptor defect, demonstrable by NaF activation, not corrected by guanyl nucleotides, leading to abnormal PTH-receptor adenylate cyclase coupling. PMID:6308054
Tamayo, J; Bellorin-Font, E; Martin, K J
The transcriptional cofactor CITED1 inhibits osteoblastic differentiation and blunts the stimulation of osteoblastic differentiation by parathyroid hormone (PTH). In the MC3T3-E1 osteoblastic cell line, we found that CITED1 was located predominantly in the cytoplasm and that hPTH(1-34) increased translocation of CITED1 from the cytoplasm to the nucleus. This response to hPTH(1-34) was not observed when all 9 serine residues within the 63-84 domain of CITED1 were mutated to alanines (CITED1 9S>A) or when a single serine to alanine mutation was made at position 79 (CITED1 S(79)>A). CITED1 containing mutations of these 9 serines to glutamic acid (9S>E) retained the same nuclear translocation response to hPTH(1-34) as the wild type CITED1. ALP activity and formation of mineralized nodules were inhibited in cells transfected with pcDNA3-CFP-CITED1 or with pcDNA3-CFP-CITED1 9S>E with or without hPTH(1-34) treatment (all P<0.05); these changes were not observed using CITED1 9S>A. Cells exposed to intermittent treatment with hPTH(1-34) expressed more ALP2, Runx2 and osteocalcin than vehicle-treated cells. These effects of hPTH(1-34) were inhibited in cells transfected with pcDNA3-CFP-CITED1 or pcDNA3-CFP-CITED1 9S>E, but were slightly enhanced by the alanine mutants. PKC activator (TPA) increased nuclear translocation of CITED1, whereas a PKC inhibitor (Go6983) blunted the effect of hPTH(1-34) on the nuclear translocation of wildtype CITED1 but not of CITED1 S(79)>E. The data indicated that serine phosphorylation at position 79 in the 63-84 domain is associated with PKC activation, and is required for both CITED1 nuclear translocation induced by PTH and the negative effects of CITED1 on osteoblastic differentiation and mineralization. PMID:25049079
Lin, Zhen; Feng, Ruiqiang; Li, Junqing; Meng, Yue; Yuan, Liang; Fu, Zhaozong; Guo, Jun; Bringhurst, F Richard; Yang, Dehong
Immunoassays utilizing commercial kits designed for diagnostic use can be adapted and validated to meet Good Laboratory Practice (GLP) requirements to support pharmacokinetic (PK) studies. We illustrate in this paper a systematic approach for commercial kit evaluation and GLP-compliant method validation to establish selectivity, sensitivity, linearity, accuracy, precision and stability. Immunoassay kits for human parathyroid hormone (hPTH) quantification from three different vendors were assessed in a side-by-side comparison for their suitability for the PK analysis of recombinant humanPTH (rhPTH) in EDTA plasma. Two immunoradiometric (IRMA) assay kits and one immunoluminometric assay (ILMA) kit were evaluated. Since PTH is present as an endogenous component of human plasma, QC preparation in the biological matrix was handled differently than for a xenobiotic drug compound. The endogenous concentration of PTH was determined in plasma samples from 32 individual lots using the three kits. The lots with the lowest endogenous concentrations of PTH were selected, pooled to form the low QC and spiked with rhPTH to prepare the mid and high QCs. Four evaluation batches were run with each of the three commercial kits to evaluate reference standard linearity, and QC accuracy and precision. Selectivity against PTH peptide fragments PTH(7-84) and PTH(3-84) were assessed by cross-reactivity and accurate spike-recovery to the QC samples at two concentrations. One of the kits was chosen for full method validation because it had the lowest cross-reactivity against hPTH fragments (3-84) and (7-84), a wider dynamic range and the least total error. The accuracy and precision from six validation batches of the QCs were Sukovaty, Richard L; Lee, Jean W; Fox, John; Toney, Karen; Papac, Damon I; Grover, Thomas A; Wells, David S 2006-09-18
In addition to its basic role in the metabolism of purine nucleotides, xanthine oxidoreductase (XOR) is involved in the generation of oxygen-derived free radicals and production and metabolic fate of nitric oxide (NO). Growth hormone (GH) and Vitamin E (E) have been shown previously to modify immune response to infection. Our objective was to determine in heifers the effect of endotoxin challenge (LPS; 3.0 microg/kg BW, i.v. bolus, Escherichia coli 055:B5) on xanthine oxidase (XO) activity in plasma and liver and the modification of this response by daily treatment with recombinant GH (0.1 mg/kg BW, i.m., for 12 days) or GH+E (E: mixed tocopherol, 1000 IU/heifer, i.m., for 5 days). In experiment 1, 16 heifers ( 348.7 +/- 6.1 kg) were assigned to control (C, daily placebo injections), GH, or GH+E treatments and were challenged with two consecutive LPS injections (LPS1 and LPS2, 48 h apart). After LPS1, plasma XO activity increased 290% (P < 0.001) at 3 h, reached peak (430%) at 24 h and returned to basal level by 48 h after LPS2. XO responses (area under the time x activity curve, AUC) were greater after LPS1 than LPS2 (P< 0.001). Total plasma XO responses to LPS (AUC, LPS1+LPS2) were augmented 55% (P < 0.05) over C with GH treatment but diminished to C responses in GH+E. There was a linear relationship (r2 = 0.605, P < 0.001) between total response in plasma XO activity and plasma nitrate + nitrate concentration. In experiment 2, 24 heifers ( 346 +/- 6 kg) were assigned to C or GH treatments and liver biopsy samples were obtained at 0, 3, 6, and 24h after a single LPS challenge. Hepatic XO activities increased 63.3% (P < 0.05) 6 h after single LPS challenge and remained elevated at 24 h (100.1%, P < 0.01) but were not affected by GH treatment. Results indicate that LPS-induced increases in plasma XO activity could be amplified by previous GH treatment but attenuated by E administration. The data also suggest that E may be effective in controlling some mediators of immune response associated with increased production of NO via the effect on XO activity and its production of superoxide anion as well as uric acid. PMID:15063924
Kahl, S; Elsasser, T H
Levels of persistent organic pollutants (POP), such as polychlorinated biphenyls (PCB), are high in many Arctic top predators, including the Arctic fox (Vulpes lagopus). The aim of this study was to examine possible endocrine-disruptive effects of dietary POP exposure in male juvenile Arctic foxes in a controlled exposure experiment. The study was conducted using domesticated farmed blue foxes (Vulpes lagopus) as a model species. Two groups of newly weaned male foxes received a diet supplemented with either minke whale (Baleneoptera acutorostrata) blubber that was naturally contaminated with POP (exposed group, n?=?5 or 21), or pork (Sus scrofa) fat (control group, n?=?5 or 21). When the foxes were 6 mo old and had received the 2 diets for approximately 4 mo (147 d), effects of the dietary exposure to POP on plasma concentrations of testosterone (T), thyroid hormones (TH), thyroid-stimulating hormone (TSH), retinol (vitamin A), and tocopherol (viramin E) were examined. At sampling, the total body concentrations of 104 PCB congeners were 0.1 � 0.03 ?g/g lipid weight (l.w.; n?=?5 [mean � standard deviation]) and 1.5 � 0.17 ?g/g l.w. (n?=?5) in the control and exposed groups, respectively. Plasma testosterone concentrations in the exposed male foxes were significantly lower than in the control males, being approximately 25% of that in the exposed foxes. There were no between-treatment differences for TH, TSH, retinol, or tocopherol. The results suggest that the high POP levels experienced by costal populations of Arctic foxes, such as in Svalbard and Iceland, may result in delayed masculine maturation during adolescence. Sex hormone disruption during puberty may thus have lifetime consequences on all aspects of reproductive function in adult male foxes. PMID:23030655
Hallanger, Ingeborg G; J�rgensen, Even H; Fuglei, Eva; Ahlstr�m, �ystein; Muir, Derek C G; Jenssen, Bj�rn Munro
This study aimed to evaluate the effects of hormone replacement therapy (HRT), known to prevent osteoporosis and fractures, on markers of bone and cartilage metabolism. Furthermore, we assessed whether changes in these markers corresponded to alterations in bone mineral density and radiographic joint destructions in postmenopausal women with rheumatoid arthritis. Eighty-eight women were randomized to receive HRT, calcium, and vitamin
Helena Forsblad d'Elia; Stephan Christgau; Lars-�ke Mattsson; Tore Saxne; Claes Ohlsson; Elisabeth Nordborg; Hans Carlsten
Parathyroid carcinoma is a rare endocrine malignancy. The reported incidence is from 0.5 to 5% of primary hyperparathyroidism cases in various series. The cause is unknown, but clinical correlations with different genetic syndromes exist. Mutations in the HPRT2 gene seem to play a significant role in the pathogenesis of this disease. Men and women are equally affected, usually in the fourth or fifth decade of life. Most patients will present with signs and symptoms of hypercalcaemia. Cases of non-functioning carcinoma are exceedingly rare. Surgical resection is the most effective method of treatment and palliation. A significant proportion of patients will experience recurrence, and will need further surgical and, eventually, medical management of hypercalcaemia. The disease is progressive but slow growing. Most patients will require multiple operations to resect recurrent disease. The main cause of morbidity and mortality is the sequela of uncontrolled chronic hypercalcaemia rather than tumour burden. The current paper will review the epidemiology, pathogenesis, clinical presentation and diagnostic work-up of this disease. Surgical management in different scenarios is reviewed in detail, followed by other types of treatment and management of incurable disease. PMID:20510594
Givi, B.; Shah, J.P.
Beyond mineral metabolism, is there an interplay between FGF23 and vitamin D in innate immunity?
Fibroblast growth factor 23 (FGF23) is an "endocrine" FGF acting in the kidney as a phosphaturic hormone and a suppressor of active vitamin D, through an inhibition of the 1? hydroxylase and a stimulation of the 24 hydroxylase. Beyond its well-known effects on the bone/kidney/parathyroid axis and its deregulation during chronic kidney disease (CKD), recent evidence has revealed its direct systemic effects on cardiovascular health. In the meantime, studies have highlighted the health implications for vitamin D inside and outside CKD that also extend beyond its classical actions on mineral homeostasis and bone metabolism: vitamin D has indeed been shown to exert pluripotent non-classical effects as a modulator of immune function in monocytes, mainly through the stimulation of the antimicrobial cathelicidin. The aim of this review is to provide new insights on the interplay between FGF23 and vitamin D in innate immunity in the context of CKD. PMID:23117582
Bacchetta, Justine; Salusky, Isidro B; Hewison, Martin
Vitamin D-deficient osteomalacia due to excessive self-restrictions for atopic dermatitis.
A 34-year-old Japanese woman presented with a 2-year history of generalised bone pain, muscle weakness and gait disturbance. The patient had been following a restricted diet (without fish or dairy products) and avoiding ultraviolet exposure for 8?years to manage her worsening atopic dermatitis. Physical examination revealed generalised bone tenderness and bilateral symmetric proximal muscle weakness. Vitamin D-deficient osteomalacia was diagnosed based on the laboratory examination findings, which indicated high serum alkaline phosphatase, high intact parathyroid hormone, and low 25-hydroxyvitamin D levels. Her symptoms improved after oral active vitamin D and calcium administration. To the best our knowledge, this case is the first report of vitamin D-deficient osteomalacia in an adult patient due to excessive dietary restriction for managing atopic dermatitis. We emphasise the importance of increasing awareness of vitamin D deficiency as a risk factor for the development of osteomalacia, and caution against excessive avoidance of sun exposure and dietary restriction. PMID:25100811
Shikino, Kiyoshi; Ikusaka, Masatomi; Yamashita, Tomoko
More than two decades of pre-clinical research and two recent clinical trials have shown that progesterone (PROG) and its metabolites exert beneficial effects after traumatic brain injury (TBI) through a number of metabolic and physiological pathways that can reduce damage in many different tissues and organ systems. Emerging data on 1,25-dihydroxyvitamin D3 (VDH), itself a steroid hormone, have begun to provide evidence that, like PROG, it too is neuroprotective, although some of its actions may involve different pathways. Both agents have high safety profiles, act on many different injury and pathological mechanisms, and are clinically relevant, easy to administer, and inexpensive. Furthermore, vitamin D deficiency is prevalent in a large segment of the population, especially the elderly and institutionalized, and can significantly affect recovery after CNS injury. The combination of PROG and VDH in pre-clinical and clinical studies is a novel and compelling approach to TBI treatment. PMID:19394357
Cekic, Milos; Sayeed, Iqbal; Stein, Donald G.
The Role of Vitamin D in Autoimmune Hepatitis
Autoimmune hepatitis is an inflammation of the liver characterized by the presence of peri-portal hepatitis, hypergammaglobulinemia, and the serum autoantibodies. The disease is classified into 2 distinct types according to the nature of auto-antibodies. Disturbances of the calcium-parathyroid hormone-vitamin D axis are frequently associated with chronic liver disease. Patients with AIH have a high prevalence of vitamin D deficiency. Genetic studies have provided the opportunity to determine which proteins link vitamin D to AIH pathology, namely, the major histocompatibility complex class II molecules, vitamin D receptors, toll-like receptors, cytotoxic T lymphocyte antigen-4, cytochrome P450 CYP2D6, regulatory T cells (Tregs) and the forkhead/winged helix transcription factor 3. Vitamin D also exerts its effect on AIH through non-genomic factors, namely, mitogen-activated protein kinase signaling pathways, ??T cells, interferon-gamma nitric oxide synthase, and reactive oxygen stress. In conclusion, vitamin D may have a beneficial role in AIH and improves liver function in concanavalin A-induced mouse AIH. Calcitriol is best used for AIH because it is the active form of a vitamin D3 metabolite and its receptors are present in sinusoidal endothelial cells, Kupffer cells, stellate cells of normal livers, and the biliary cell line. PMID:24171052
Luong, Khanh vinh quoc; Nguyen, Lan Thi Hoang
Low concentrations of 25-hydroxyvitamin D have been consistently associated with cardiovascular disease (CVD) in many observational studies. In an analysis published in this issue of the American Journal of Epidemiology, Welles et al. (Am J Epidemiol. 2014;179(11):1279-1287) used data from 946 participants with stable CVD who were enrolled in the Heart and Soul Study (San Francisco Bay Area, 2000-2012) and found that the association of low 25-hydroxyvitamin D with increased secondary CVD event risk was attenuated after adjustment for parathyroid hormone level, suggesting that parathyroid hormone may mediate this association. They used observational data to gain insight into potential mechanisms underlying the association between vitamin D and CVD risk. Their study focused on secondary CVD events, whereas many previous observational studies have focused on incident CVD events among persons without a history of CVD. In this commentary, we place the study by Welles et al. in context with the existing literature and propose future directions for vitamin D research. We highlight a number of methodological concepts that are important in analyzing vitamin D data, including racial differences in vitamin D concentrations and adjustment for seasonal variation in vitamin D concentrations. We agree that randomized controlled trials should be conducted before making guidelines for screening and treating vitamin D deficiency for the prevention of CVD events. PMID:24699787
Schneider, Andrea L C; Michos, Erin D
Parathyroid function in chronic kidney disease: role of FGF23-Klotho axis.
The parathyroid gland plays a central role in the regulation of mineral metabolism. In patients with chronic kidney disease (CKD), circulating levels of parathyroid hormone (PTH) are progressively increased as kidney function declines, as a result of phosphate retention, hypocalcemia, decreased production of 1,25-dihydroxyvitamin D [1,25(OH)2D], endogenous changes within the parathyroid gland, and skeletal resistance to the actions of PTH. In addition, the identification of fibroblast growth factor 23 (FGF23) and its cofactor Klotho offers important implications for the deeper understanding of disordered mineral metabolism in CKD. In early CKD, increased FGF23 to maintain neutral phosphate balance results in suppression of renal 1,25(OH)2D production and thereby triggers the early development of secondary hyperparathyroidism. FGF23 also acts directly on the parathyroid to decrease PTH synthesis and secretion, but this effect is blunted in advanced stages of CKD, due to decreased expression of the Klotho-FGF receptor 1 complex and increased concentrations of C-terminal FGF23 that competes with full-length FGF23 for binding to the receptor complex. Recent clinical studies also reported that high levels of FGF23 are associated with morbidity and mortality as well as treatment resistance to active vitamin D, suggesting the potential of FGF23 as a novel biomarker to guide treatment of disordered phosphate metabolism in CKD. This review will discuss the pathogenesis of secondary hyperparathyroidism, particularly focusing on the emerging role of the FGF23-Klotho axis in patients with CKD. PMID:23652554
Koizumi, Masahiro; Komaba, Hirotaka; Fukagawa, Masafumi
Hormones are your body's chemical messengers. They travel in your bloodstream to tissues or organs. They work ... glands, which are special groups of cells, make hormones. The major endocrine glands are the pituitary, pineal, ...
Oral active vitamin D is associated with improved survival in hemodialysis patients.
Injection of active vitamin D is associated with better survival of patients receiving chronic hemodialysis. Since in many countries oral active vitamin D administration is the most common form of treatment for secondary hyperparathyroidism we determined the survival benefit of oral active vitamin D in hemodialysis patients from six Latin America countries (FME Register as part of the CORES study) followed for a median of 16 months. Time-dependent Cox regression models, after adjustment for potential confounders, showed that the 7,203 patients who received oral active vitamin D had significant reductions in overall, cardiovascular, infectious and neoplastic mortality compared to the 8,801 patients that had not received vitamin D. Stratified analyses found a survival advantage in the group that had received oral active vitamin D in 36 of the 37 strata studied including that with the highest levels of serum calcium, phosphorus and parathyroid hormone. The survival benefit of oral active vitamin D was seen in those patients receiving mean daily doses of less than 1 microg with the highest reduction associated with the lowest dose. Our study shows that hemodialysis patients receiving oral active vitamin D had a survival advantage inversely related to the vitamin dose. PMID:18633342
Naves-D�az, Manuel; Alvarez-Hern�ndez, Daniel; Passlick-Deetjen, Jutta; Guinsburg, Adrian; Marelli, Cristina; Rodriguez-Puyol, Diego; Cannata-And�a, Jorge B
Transplantation of the parathyroid glands in man: clinical indications and results.
The physiologic function of human parathyroid autografts and allografts has not been demonstrated conclusively. During the past 30 months, we have transplanted parathyroid glands in 29 patients and tested their functional status. One immunosuppressed aparathyroid patient received a parathyroid allograft from a parent who previously had been his renal transplant donor. Twenty-seven patients with renal failure and secondary hyperparathyroidism received parathyroid autografts immediately after total parathyroidectomy, and one patient received a parathyroid autograft at the time of total parathyroidectomy for primary chief cell hyperplasia. At transplantation 1 times 1 mm. parathyroid pieces were grafted into the forearm musculature. Of 11 transplanted patients (one allograft and ten autografts) followed for 1 year, ten are normocalcemic; only two (autografted patients) are on supplemental calcium. Ten of the 29 patients have had biopsies performed, and all have had intact parathyroid architecture and intracellular secretory granules demonstrated by light and electron microscopy. Parathyroid hormone content in the grafted tissue of five patients was 179 plus or minus 118.8 ng. per milligram. In 11 random patients in whom bilateral measurements have been made, the parathyroid hormone content in the antecubital vein blood draining the grafted tissue has been markedly higher than that in the simultaneously sampled antecubital vein blood of the nongrafted arm. These data demonstrate that parathyroid autografts or allografts secret hormone and maintain a normal serum calcium in the host. PMID:1138398
Wells, S A; Gunnells, J C; Shelburne, J D; Schneider, A B; Sherwood, L M
Internalization of G protein-coupled receptors (GPCRs) and desensitization of the hormonal responses are well charac- terized in vitro for several hormonal systems. The physiolog- ical role of internalization for a GPCR receptor involved in homeostatic functions has not been established, although it has been assumed based on in vitro data. We have previously shown that phosphorylation of the PTH\\/PTHrP receptor
George S. Bounoutas; Hesham Tawfeek; Leopold F. Frohlich; Ung-il Chung; Abdul B. Abou-Samra
Aplastic osteodystrophy without aluminum: The role of �suppressed� parathyroid function
Aplastic osteodystrophy without aluminum: The role of �suppressed� parathyroid function. We evaluated 259 dialysis patients using serum parathyroid hormone (PTH, IRMA; normal range 1 to 5.5 pM or 10 to 55 pg\\/ml), the deferoxamine infusion test and iliac crest bone biopsy to determine the various forms of renal osteodystrophy and their risk factors. Although half of the biopsied patients had
Gavril Hercz; Y Pei; C Greenwood; A Manuel; C Saiphoo; W G Goodman; G V Segre; S Fenton; D J Sherrard
Hormonal Control of Calcium Homeostasis
Calcium homeostasis in the extracellular fluid is tightly controlled and defended physiologically. Hypercalce- mia always represents considerable underlying pathol- ogy and occurs when the hormonal control of calcium homeostasis is overwhelmed. The major hormones that are responsible for normal calcium homeostasis are parathyroid hormone and 1,25-dihydroxyvitamin D; these hormones control extracellular fluid calcium on a chronic basis. Over- or underproduction
Gregory R. Mundy; Theresa A. Guise
Background To date, few studies have investigated serum vitamin D status in patients with inherited ichthyosis. The aim of this study was to determine the prevalence of vitamin D deficiency (defined as serum level <10�ng/mL) in a French cohort of patients and to identify associated risk factors. Methods This was a prospective observational study performed in a hospital reference center with expertise for rare skin diseases. Patients� clinical characteristics were recorded. Serum concentration of 25-hydroxyvitamin D and parathyroid hormone were determined. For patients with vitamin D deficiency, serum calcium, serum phosphorus and bone mineral density were also investigated. Comparisons between groups (25-hydroxyvitamin D <10�ng/mL versus ?10�ng/mL) were conducted by univariate and multivariate logistic regression. Results Of the 53 included patients, 47 (88.7%) had serum 25-hydroxyvitamin D below the optimal level of 30�ng/mL: 18 (34%) had vitamin D sufficiency, 14 (26.4%) had vitamin D insufficiency, and 15 (28.3%) had vitamin D deficiency. A negative linear correlation was found between 25-hydroxyvitamin D and parathyroid hormone levels for the whole study population. Serum calcium and phosphorus levels were normal for the 15 patients with vitamin D deficiency. Bone mineral density was investigated for 11 of these latter 15 patients, and six of them had osteopenia. Winter/spring seasons of vitamin D measurement, severity of ichthyosis, and phototypes IV�VI were identified as independent risk factors for vitamin D deficiency. Conclusions Clinicians should be aware of the risk of vitamin D deficiency in the management of patients with inherited ichthyosis, especially in winter and spring, and in case of dark skin or severe disease. PMID:25091406
Radionuclide imaging of parathyroid tumors: historical perspectives and newer techniques
The increasing use of automated blood chemistry screens for serum calcium levels along with improved methods in measuring parathyroid hormone (PTH) levels have made the diagnosis of parathyroid disease a common clinical problem. Parathyroid adenomas account for the majority of primary hyperparathyroidism with diffuse hyperplasia and parathyroid carcinoma occurring less frequently. Early scintigraphic techniques to identify enlarged parathyroids used selenomethionine-75 which was considered to be incorporated into PTH. In general, the sensitivity of scanning the neck using this tracer was related to the size of the enlarged parathyroid, but in large series, the overall sensitivity was less than 50%. Recent work by Ferlin et al, using a Technetium-99m/Thallium-201 subtraction scintigraphic technique has yielded a sensitivity of 92% in identifying pathologically enlarged parathyroid glands. Winzelberg et al modified this technique to allow imaging the mediastinum plus simplifying the subtraction method. In a prospective study with high-resolution sonography, similar sensitivities and specificities were found with sonography and scintigraphy. Tl-201/Tc-99m pertechnetate subtraction scintigraphy appears to be an accurate technique in identifying pathologic parathyroid enlargement. Its ultimate role in the evaluation of patients with suspected hyperparathyroidism still needs to be determined. 37 references.
Winzelberg, G.G.; Hydovitz, J.D.
[Overdose or hypersensitivity to vitamin D?].
Vitamin�D intoxication with severe hypercalcemia is rare in the neonatal and infancy period. Through nine cases of hypercalcemia, secondary to taking 600,000�units of vitamin�D (Sterogyl(�)), a review of vitamin�D requirements and possible mechanisms of toxicity including hypersensitivity to this vitamin will be discussed. We report nine cases of babies admitted to our department between the ages of 25 and 105�days for treatment of severe dehydration. The pregnancies were normal, with no incidents at delivery. Clinical signs were dominated by weight loss, vomiting, and fever. Examination on admission revealed dehydration whose degree ranged from 8 to 15% with preserved diuresis and loss weight between 100 and 1100�g. Laboratory tests objectified hypercalcemia between 113 and 235mg/L, hypercalciuria (urinary calcium/creatinine mmol/mmol >0.5), and a low-level of parathyroid hormone. The vitamin�D values in nine patients were toxic (344-749�nmol/L; normal >50�nmol/L; toxicity if >250�nmol/L). Abdominal ultrasound objectified renal nephrocalcinosis in seven patients. The DNA study, performed in eight patients, did not reveal a mutation of the vitamin�D 24-hydroxylase gene (CYP24A1). The treatment consisted of intravenous rehydration with treatment of hypercalcemia (diuretics and corticosteroids). Serum calcium returned to the normal range within 4-50�days, with weight gain progressively over the following weeks. The follow-up (2�years for the oldest case) showed the persistence of images of nephrocalcinosis. Genetic susceptibility and metabolic differences appear to modulate the threshold of vitamin�D toxicity. However, respect for recommended doses, recognized as safe in a large study population, reduces the risk of toxicity. PMID:25129320
Hmami, F; Oulmaati, A; Amarti, A; Kottler, M-L; Bouharrou, A
Circulating 25-hydroxyvitamin D [25(OH)D] is generally considered the means by which we define nutritional vitamin D status. There is much debate, however, with respect to what a healthy minimum level of circulation 25(OH)D should be. Recent data using various biomarkers such as intact parathyroid hormone (PTH), intestinal calcium absorption, and skeletal density measurements suggest this minimum level to be 80 nmol (32 ng/mL). Surprisingly, the relationship between circulating vitamin D3 and its metabolic product�25(OH)D3 has not been studied. We investigated this relationship in two separate populations: the first, individuals from Hawaii who received significant sun exposure; the second, subjects from a lactation study who received up to 6,400 IU vitamin D3/day for six months. Results: 1) The relationship between circulating vitamin D3 and 25(OH)D in both groups was not linear, but appeared saturable and controlled; 2) Optimal nutritional vitamin D status appeared to occur when molar ratios of circulating vitamin D3 and 25(OH)D exceeded 0.3; at this point, the Vmax of the 25-hydroxylase appeared to be achieved. This was achieved when circulating 25(OH)D exceeded 100 nmol. We hypothesize that as humans live today, the 25-hydroxylase operates well below its Vmax because of chronic substrate deficiency, namely vitamin D3. When humans are sun (or dietary) replete, the vitamin D endocrine system will function in a fashion as do these other steroid synthetic pathways, not limited by substrate. Thus, the relationship between circulating vitamin D and 25(OH)D may represent what �normal� vitamin D status should be. PMID:17218096
Hollis, Bruce W.; Wagner, Carol L.; Drezner, Mark K.; Binkley, Neil C.
Vitamin D Status and Outcomes After Renal Transplantation
Kidney transplant recipients usually have low vitamin D levels, especially in the early posttransplantation period, but the association between vitamin D status with renal outcomes is not well described in this population. Here, we studied a prospective cohort of 634 kidney recipients who underwent transplantation at a single institution between January 2005 and June 2010. In this cohort, low 25-hydroxyvitamin D concentrations 3 months after transplantation did not predict early death or graft loss but were independently associated with lower measured GFR at 12 months (P=0.001) and higher risk for interstitial fibrosis and tubular atrophy (P=0.01). In contrast, levels of calcium, phosphorus, calcitriol, parathyroid hormone, or fibroblast growth factor-23 were not consistently associated with any of the studied outcomes. In conclusion, low 25-hydroxyvitamin D concentration measured 3 months after transplantation is an independent risk factor for interstitial fibrosis progression and is associated with a lower GFR 1 year after transplantation. PMID:23539758
Girard, Delphine; Anglicheau, Dany; Canaud, Guillaume; Souberbielle, Jean Claude; Kreis, Henri; Noel, Laure Helene; Friedlander, Gerard; Elie, Caroline; Legendre, Christophe; Prie, Dominique
Aim. To report vitamin D status and its impact on metabolic parameters in people in the United Arab Emirates with obesity and type 2 diabetes (T2D). Methodology. This cross-sectional study included 309 individuals with obesity and T2D who were randomly selected based on study criteria. Serum concentrations of 25-hydroxy vitamin D (s-25(OH)D), calcium, phosphorus, parathyroid hormone, alkaline phosphatase, glycemic profile, and cardiometabolic parameters were assessed in fasting blood samples, and anthropometric measurements were recorded. Results. Vitamin D deficiency (s-25(OH)D < 50?nmol/L) was observed in 83.2% of the participants, with a mean s-25(OH)D of 33.8 � 20.3?nmol/L. Serum 25(OH)D correlated negatively (P < 0.01) with body mass index, fat mass, waist circumference, parathyroid hormone, alkaline phosphatase, triglycerides, LDL-cholesterol, and apolipoprotein B and positively (P < 0.01) with age and calcium concentration. Waist circumference was the main predictor of s-25(OH)D status. There was no significant association between serum 25(OH)D and glycemic profile. Conclusion. There is an overwhelming prevalence of vitamin D deficiency in our sample of the Emirati population with obesity and T2D. Association of s-25(OH)D with body mass index, waist circumference, fat mass, markers of calcium homeostasis and cardiometabolic parameters suggests a role of vitamin D in the development of cardiometabolic disease-related process. PMID:25371907
Ahmed, Solafa M.; Skaria, Sijomol; Abusnana, Salah
Evidence indicates that optimal nutrition plays a role in bone formation and maintenance. Besides major components of mineralization such as calcium, phosphorus, and vitamin D, other nutrients like boron and fluoride have beneficial role, too. In this study, 34 male Wistar rats were divided into five groups: control diet, fluoride, fluoride + boron, fluoride + calcium + vitamin D, and fluoride + boron + calcium + vitamin D. Boron equal to 1.23 mg, calcium and vitamin D equal to 210 mg + 55 IU and fluoride equal to 0.7 mg/rat/day was added to their drinking water for 8 weeks. Plasma blood samples and bones were collected. Findings are evidence that fluoride + boron intake revealed significant positive effects on bone mechanical properties and bone metabolic hormones. These findings suggest that combined intake of these two elements has beneficial effects on bone stiffness and breaking strength comparing to even calcium + vitamin D supplementation. This evidence dealing with health problems related to bone and skeletal system in humans should justify further investigation of the role of boron and fluoride with other elements in relation to bone. PMID:22782709
Ghanizadeh, G; Babaei, M; Naghii, Mohammad Reza; Mofid, M; Torkaman, G; Hedayati, M
Can we use 99mTc-MIBI in functional studies of the parathyroid gland?
The usefulness of technetium-99m-sestamibi (99mTc-MIBI) in patients with secondary hyperparathyroidism on haemodialysis was assessed. We studied 33 patients with parathyroid scintigraphy with i.v. (99mTc-MIBI). Static images in a scintillation camera were taken at 15 and 120 min after the injection. With P x Ca<80, we performed an inhibition test with calcitriol i.v. 2 microg, three times a week, for 2 weeks. The MIBI study and assessment of intact parathyroid hormone (iPTH) were performed before (baseline study) and after inhibition. A 'focal positive study' corresponded to one or more areas of abnormal hypercaptation in relation to surrounding thyroid tissue seen in early images and persisting in later images, and a 'negative study' did not correspond to the previous image. In the baseline study, iPTH in the positive MIBI group was significantly greater than in the negative group. Eight positive MIBI patients had a bone biopsy; six corresponded to severe osteitis fibrosa and two to mild osteitis fibrosa. In the negative MIBI group, four of the six patients who had bone biopsy had mild forms of osteitis fibrosa (Fisher=0.03); the other two had low turnover forms. A positive inhibition test was defined when the basal uptake disappeared after calcitriol administration. In these patients, we observed a significant decrease of iPTH, not observed in the negative inhibition test. In 10 patients who had been parathyroidectomized, those with alpha positive basal MIBI result had a nodular parathyroid hyperplasia. We conclude that a scintigraphic parathyroid study with 99mTc-MIBI showed a good correlation with functional parathyroid status. With the same inhibition test, only some glands were inhibited, suggesting that this could be the expression of different vitamin D receptor densities in inhibited glands and/or a different kind of proliferation in those glands. This test would be of value in functional studies when a therapeutic decision must be made. PMID:9580537
Ambrosoni, P; Heuguerot, C; Olaizola, I; Acu�a, G; Fajardo, L; Petraglia, A; Caorsi, H; L�pez, J; Kurdian, M; Jorgetti, V; Azn�rez, A
Blood vascular bed and pericapillary space in rat parathyroid glands.
The blood vascular bed and pericapillary space of the rat parathyroid gland were studied by scanning electron microscopy of vascular casts, freeze-cracked tissue blocks, and NaOH-treated tissue specimens. The findings were supplemented by transmission light and electron microscopy of sectioned tissue samples. The rat parathyroid gland contained a rich network of freely anastomosing capillaries. These capillaries were surrounded by marked pericapillary spaces that were demarcated by basal lamina of both capillaries and parenchymal cells. The pericapillary spaces contained many collagen fibrils and frequently issued some projections running deep into the sheets of parathyroid cells. The latter projections may be useful to supply the parenchymal cells located far from the capillaries. The collagen fibrils may regulate the flow of tissue fluid in the pericapillary space and convey parathyroid hormone, which is released at the apicolateral domain, into the capillaries. PMID:8580506
Murakami, T; Tanaka, T; Taguchi, T; Ohtsuka, A; Kikuta, A
Vitamin D receptor activation and survival in chronic kidney disease.
Replacement of activated vitamin D has been the cornerstone of therapy for secondary hyperparathyroidism (SHPT). Recent findings from several large observational studies have suggested that the benefits of vitamin D receptor activators (VDRA) may extend beyond the traditional parathyroid hormone (PTH)-lowering effect, and could result in direct cardiovascular and metabolic benefits. The advent of several new analogs of the activated vitamin D molecule has widened our therapeutic armamentarium, but has also made therapeutic decisions more complicated. Treatment of SHPT has become even more complex with the arrival of the first calcium-sensing receptor (CSR) agonist (cinacalcet hydrochloride) and with the uncovering of novel mechanisms responsible for SHPT. We provide a brief overview of the physiology and pathophysiology of SHPT, with a focus on vitamin D metabolism, and discuss various practical aspects of VDRA therapy and its reported association with survival in recent observational studies. A detailed discussion of the available agents is aimed at providing the practicing physician with a clear understanding of the advantages or disadvantages of the individual medications. A number of open questions are also analyzed, including the present and future roles of CSR agonists and 25(OH) vitamin D replacement. PMID:18288097
Kovesdy, C P; Kalantar-Zadeh, K
NASA Technical Reports Server (NTRS)
PTH treatment can result in dramatic increases in cancellous bone volume in normal and osteopenic rats. However, this potentially beneficial response is only observed after pulsatile treatment; continuous infusion of PTH leads to hypercalcemia and bone abnormalities. The purpose of these studies was to determine the optimal duration of the PTH pulses. A preliminary study revealed that human PTH-(1-34) (hPTH) is cleared from circulation within 6 h after sc administration of an anabolic dose of the hormone (80 microg/kg). To establish the effects of gradually extending the duration of exposure to hPTH without increasing the daily dose, we programmed implanted Alzet osmotic pumps to deliver the 80 microg/kg x day dose of the hormone during pulses of 1, 2, and 6 h/day, or 40 microg/kg x day continuously. Discontinuous infusion was accomplished by alternate spacing of external tubing with hPTH solution and sesame oil. After 6 days of treatment, we evaluated serum chemistry and bone histomorphometry. As negative and positive controls, groups of rats received pumps that delivered vehicle only and 80 microg/kg x day hPTH by daily sc injection, respectively. Dynamic and static bone histomorphometry revealed that the daily sc injection and 1 h/day infusion dramatically increased osteoblast number and bone formation in the proximal tibial metaphysis, whereas longer infusion resulted in systemic side-effects, including up to a 10% loss in body weight, hypercalcemia, and histological changes in the proximal tibia resembling abnormalities observed in patients with chronic primary hyperparathyroidism, including peritrabecular marrow fibrosis and focal bone resorption. Infusion for as little as 2 h/day resulted in minor weight loss and changes in bone histology that were intermediate between sc and continuous administration. The results demonstrate that the therapeutic interval for hPTH exposure is brief, but that programmed administration of implanted hormone is a feasible alternative to daily injection as a route for administration of the hormone.
Dobnig, H.; Turner, R. T.
Experimental induction of parathyroid adenomas in the rat
Neonatal inbred Wistar albino rats were given either 5 or 10 microCi radioiodine (/sup 131/I) within 24 hours of birth. After weaning, animals were placed on diets high, normal, or deficient in vitamin D3 (cholecalciferol) for periods up to 2 years. In animals aged 12 months and older, adenomas were found in 0 of 67 unirradiated controls, in 22 of 67 given 5 microCi /sup 131/I, and in 25 of 67 given to microCi /sup 131/I. The incidence of tumors in irradiated animals was highest (55%) in those on a low-vitamin D diet and lowest (20%) in those on a high-vitamin D diet. Plasma calcium levels were significantly increased by the high-vitamin D diet, but the low-vitamin D diet did not lead to any significant decrease as compared to the calcium levels of the normal vitamin D diet group. Small but significant calcium increases were found in tumor-bearing animals. These findings indicate that parathyroid tumors in the rat can be induced by radiation and that their incidence is strongly influenced by dietary vitamin D content. The possibility that metabolites of vitamin D3 may influence parathyroid growth and tumor formation directly is discussed.
Wynford-Thomas, V.; Wynford-Thomas, D.; Williams, E.D.
\\u000a The most common parathyroid gland pathology in primary hyperparathyroidism is parathyroid adenoma, followed by hyperplasia\\u000a and carcinoma. Adenoma, hyperplasia, and carcinoma have distinct molecular genetic profiles, however, their pathologic features\\u000a are often overlapping leading to significant diagnostic dilemma, even on permanent sections. Final diagnosis must be arrived\\u000a at after taking into consideration the abnormal gland, the status of the remaining
Manju L. Prasad; Ashraf Khan
Parathyroid carcinoma: a silent presentation
Primary hyperparathyroidism is most commonly diagnosed in the setting of benign parathyroid adenoma(s). However, it can also rarely be caused by parathyroid malignancy and when it is, the clinical manifestations far supercede the presentation of benign parathyroid adenoma. We report a case of suspected benign parathyroid adenoma induced primary hyperparathyroidism in which pathologic diagnosis of parathyroid carcinoma was made. Due to the lack of signs and symptoms, this indicates parathyroid malignancy can be masked clinically as benign adenomas, until a histologic diagnosis can be ascertained.
Lal, Karan; Chang, Robert; Mandava, Nageswara
PTH-C1: a rat continuous cell line expressing the parathyroid phenotype.
The lack of a continuous cell line of epithelial parathyroid cells able to produce parathyroid hormone (PTH) has hampered the studies on in vitro evaluation of the mechanisms involved in the control of parathyroid cell function and proliferation. The PT-r cell line was first established from rat parathyroid tissue in 1987, but these cells were known to express the parathyroid hormone-related peptide (Pthrp) gene, but not the Pth gene. In an attempt to subclone the PT-r cell line, a rat parathyroid cell strain was isolated and named PTH-C1. During 3 years, in culture, PTH-C1 cells maintained an epithelioid morphology, displaying a diploid chromosome number, a doubling time around 15 h during the exponential phase of growth, and parathyroid functional features. PTH-C1 cell line produces PTH and expresses the calcium sensing receptor (Casr) gene and other genes known to be involved in parathyroid function. Most importantly, the PTH-C1 cells also exhibit an in vitro secretory response to calcium. Altogether these findings indicate the uniqueness of the PTH-C1 cell line as an in vitro model for cellular and molecular studies on parathyroid physiopathology. PMID:24627164
Fabbri, Sergio; Ciuffi, Simone; Nardone, Valeria; Gomes, Ana Rita; Mavilia, Carmelo; Zonefrati, Roberto; Galli, Gianna; Luzi, Ettore; Tanini, Annalisa; Brandi, Maria Luisa
Response of dog parathyroid glands to short-term alterations of serum calcium
Parathyroid (PT) glands of dogs were exposed to low or high serum calcium by infusion of either EGTA or CaCl2. Infusion of EGTA resulted in an increase of parathyroid hormone (PTH) and infusion of CaCl2, in a decrease of this hormone. The PT glands excised either at the beginning or at the end of the infusions were examined by electron
P. Wild; M. Becker
Vitamin D study in pregnant women and their babies
Background and objectives: Vitamin D deficiency is very common in pregnant women. Deficiencies have been prevalent even in studies where over 90% of the women took prenatal vitamins. The current guidelines for vitamin D intake during pregnancy of 200�400 IU has little scientific support and has been recently challenged. We conducted this study to determine the prevalence of vitamin D deficiency among pregnant women and to evaluate the effectiveness and level of weekly oral 50,000 IU of vitamin D supplementation for the mother and the newborn. Setting and design: Prospective study at Hamad Medical Corporation outpatient unit and delivery room. Patients and Methods: Ninety seven pregnant women were recruited in their first trimester between December 2007 and March 2010. Weekly oral vitamin D (50,000 IU) were prescribed after an initial testing for serum level of 25-hydroxyvitamin D, parathyroid hormone, calcium, phosphorus, total protein and albumin. Other multivitamins supplementations were allowed during pregnancy. The same tests were repeated at each trimester. Umbilical cords vitamin D levels were determined at birth. Results: Out of 97 patients, 8 patients dropped out from the study for several reasons, and 19 patients had pregnancy loss. Data were available for 97�women in the first trimester, 78 women in the second trimester and 61 women in the third trimester. The mean level of vitamin D level in the first trimester and prior to starting vitamin D supplementation was 17.15�ng/ml, 29.08�ng/ml in the second trimester, 27.3�ng/ml in third trimester and 22.36�ng/ml in newborns. There were no toxic levels of vitamin D in any of the women at the second or third trimesters or in the newborns. The mean levels of vitamin D in the second and third trimester were not significantly different in those women who were taking multivitamin supplementation and those who were not. Conclusion: Weekly doses of 50,000 vitamin D during pregnancy maintains acceptable vitamin D level during pregnancy and the newborn's vitamin D level correlates with the mother's levels. PMID:25003056
Al Emadi, Samar; Hammoudeh, Mohammed
Background: Inadequate levels of vitamin D increase the risk of osteoporosis, a highly prevalent condition in patients with traumatic spinal cord injury (SCI). Reduced sunlight and dark skin further contribute to low vitamin D levels. Objectives: To compare serum 25-hydroxy vitamin D [vitamin D25(OH)] levels in acute and chronic SCI and to explore seasonal and ethnic differences among patients with acute and chronic SCI. Patients/Methods: Patients (N ?=? 96) aged 19 to 55�years with C3-T10 motor complete SCI participated. Acute SCI was 2 to 6�months after injury, whereas chronic SCI was at least 1�year from injury. Serum vitamin D25(OH), calcium, and parathyroid hormone were drawn during summer or winter months. Vitamin D deficiency (<13�ng/mL), insufficiency (<20�ng/mL), and subtherapeutic (<32�ng/mL) levels were compared for all groups. A 3-way analysis of covariance was adopted to determine significant main effects of season, chronicity, and ethnicity. Interactions between season and chronicity, season and ethnicity, and chronicity and ethnicity were evaluated. Evaluation of a 3-way interaction among season, chronicity, and ethnicity was completed. Results: In summer, 65% of patients with acute SCI and 81% of patients with chronic SCI had subtherapeutic vitamin D levels, whereas in winter, 84% with acute SCI and 96% with chronic SCI had vitamin D25(OH) (<32ng/mL). Lower vitamin D25(OH) levels were observed in African Americans relative to whites. Significant main effects were noted for season (P ?=? 0.017), chronicity (P ?=? 0.003), and ethnicity (P < 0.001). However, interactions between 2 or more factors were not found. Conclusions: Vitamin D insufficiency and deficiency are found in the majority of patients with chronic SCI and in many with acute SCI. Initial screening for serum vitamin D25(OH) levels should be performed early in rehabilitation. Periodic monitoring in the chronic setting is highly recommended. PMID:20737793
Oleson, Christina V; Patel, Payal H; Wuermser, Lisa-Ann
Background Exposure to cigarette smoke during pregnancy leads to several adverse effects on mother and child. The purpose of this study was to evaluate the effect of being a passive smoker during pregnancy on vitamin D level and related biochemical indices including parathyroid hormone, calcium, phosphorus and alkaline phosphatase in mothers and newborns. Methods One hundred eight pregnant women and their newborns participated in a historical cohort study in two equal groups (n?=?54) with and without cigarette smoke exposure. Maternal blood and urine samples and blood samples of umbilical cord were obtained in the delivery room. Concentration of 25-hydroxy vitamin D and related biochemical indices in samples of maternal and cord blood were investigated. Exposure to cigarette smoke was evaluated through questionnaire and maternal urine and umbilical cord serum cotinine levels. Results The mean level of 25-hydroxyvitamin D in maternal serum was 9.28?�?5.19?ng/mlin exposed and 10.75?�?5.26?ng/ml in non-exposed group(p?>?0.05). The mean concentration of 25-hydroxy vitamin D in cord serum was 10.83?�?6.68?ng/ml in the exposed and 11.05?�?4.99?ng/ml in the non-exposed group(p?>?0.05). The exposed mothers had significantly higher parathyroid hormone level (p?=?0.013), lower serum calcium (p?=?0.024) and higher serum alkaline phosphatase (p?=?0.024). There was a significant correlation between maternal and umbilical cord serum 25-hydroxyvitamin D within both exposed and non-exposed groups (p?0.001). Conclusion Maternal exposure to cigarette smoking during pregnancy negatively influences serum calcium level and increase parathyroid hormone and alkaline phosphatase in mothers. PMID:23663478
The steroid hormones that play major roles in the neuroimmune regulatory network include glucocorticoids, aldosterone, estrogens, androgens and vitamin D. These hormones have cytoplasmic or nuclear receptors, which are transcription factors that directly regulate gene expression. Glucocorticoids are produced in the adrenal gland as well as the thymus and are fundamental to immune function. Physiological levels are required for the
Istvan Berczi; Eva Nagy; Edward Baral; Andor Szentivanyi
Potential for vitamin D receptor agonists in the treatment of cardiovascular disease
Vitamin D3 is made in the skin and modified in the liver and kidney to form the active metabolite, 1,25-dihydroxyvitamin D3 (calcitriol). Calcitriol binds to a nuclear receptor, the vitamin D receptor (VDR), and activates VDR to recruit cofactors to form a transcriptional complex that binds to vitamin D response elements in the promoter region of target genes. During the past three decades the field has focused mainly on the role of VDR in the regulation of parathyroid hormone, intestinal calcium/phosphate absorption and bone metabolism; several VDR agonists (VDRAs) have been developed for the treatment of osteoporosis, psoriasis and hyperparathyroidism secondary to chronic kidney disease (CKD). Emerging evidence suggests that VDR plays important roles in modulating cardiovascular, immunological, metabolic and other functions. For example, data from epidemiological, preclinical and clinical studies have shown that vitamin D and/or 25(OH)D deficiency is associated with increased risk for cardiovascular disease (CVD). However, VDRA therapy seems more effective than native vitamin D supplementation in modulating CVD risk factors. In CKD, where decreasing VDR activation persists over the course of the disease and a majority of the patients die of CVD, VDRA therapy was found to provide a survival benefit in both pre-dialysis and dialysis CKD patients. Although VDR plays an important role in regulating cardiovascular function and VDRAs may be potentially useful for treating CVD, at present no VDRA is approved for CVD, and also no serum markers, beside parathyroid hormone in CKD, exist to indicate the efficacy of VDRA in CVD. PMID:19371337
Wu-Wong, JR
Molecular Genetics of Parathyroid Disease
Background��Primary hyperparathyroidism (HPT) is often caused by a benign parathyroid tumor, adenoma; less commonly by multiglandular\\u000a parathyroid disease\\/hyperplasia; and rarely by parathyroid carcinoma. Patients with multiple tumors require wider exploration\\u000a to avoid recurrence and have increased risk for hereditary disease. Secondary HPT is a common complication of renal failure.\\u000a Improved knowledge of the molecular background of parathyroid tumor development may
Gunnar Westin; Peyman Bj�rklund; G�ran �kerstr�m
Vitamin C deficiency in the Arabidopsis mutant vtc1 causes slow growth and late flowering. This is not attributable to changes in photosynthesis or increased oxidative stress. We have used the vtc1 mutant to provide a molecular signature for vitamin C deficiency in plants. Using statistical analysis, we show that 171 genes are expressed differentially in vtc1 compared with the wild
Gabriela M. Pastori; Guy Kiddle; John Antoniw; Stephanie Bernard; Sonja Veljovic-Jovanovic; Paul J. Verrier; Graham Noctor; Christine H. Foyer
Parathyroid carcinoma in pregnancy.
A 24-year-old female patient with parathyroid carcinoma, the rarest endocrine malignancy, had two pregnancies. In the first pregnancy, she had severe nausea and fatigue. Hypercalcemia and hyperparathyroidism were diagnosed in the postpartum period. Hyperemesis gravidarum masked a diagnosis of hypercalcemia. Neck ultrasound and Tc-99m sestamibi found an enlarged lower right parathyroid gland. The gland was surgically removed, and an initial pathology report described atypical adenoma. Shortly afterward, she became pregnant again. During the second pregnancy, her calcium level was frequently controlled but was always in the normal range. Normocalcemia is explained by the specific physiology of pregnancy accompanied by hemodilution, hypoalbuminemia and maternal hypercalciuria (mediated by increased glomerular filtration). During lactation, calcium levels rose, and a new neck ultrasound showed a solitary mass in the area of prior surgery and an enlarged pretracheal lymph node. Fine needle aspiration of the solitary mass and node showed parathyroid carcinoma cells. The tumor mass was resected en bloc with the contiguous tissues and surrounding lymph nodes (pathology report; parathyroid carcinoma with metastases). Over the next five years, four consecutive surgeries were performed to remove malignant parathyroid tissue, lymph nodes and local metastases. Following the surgical procedures, no hypocalcemia was observed. More serious hypercalcemia recurred; the calcium level was difficult to control with a combination of pamidronate, cinacalcet and loop diuretic. No elements of multiple endocrine neoplasia were present. PMID:24868516
Bareti?, Maja; Tomi? Brzac, Hrvojka; Dobreni?, Margareta; Jakov?evi?, Antonia
Thyroid and parathyroid imaging
This book describes the numerous modalities currently used in the diagnosis and treatment of both thyroid and parathyroid disorders. Each modality is fully explained and then evaluated in terms of benefits and limitations in the clinical context. Contents: Production and Quality Control of Radiopharmaceutics Used for Diagnosis and Therapy in Thyroid and Parathyroid Disorders. Basic Physics. Nuclear Instrumentation. Radioimmunoassay: Thyroid Function Tests. Quality Control. Embryology, Anatomy, Physiology, and Thyroid Function Studies. Scintigraphic Thyroid Imaging. Neonatal and Pediatric Thyroid Imaging. Radioiodine Thyroid Uptake Measurement. Radioiodine Treatment of Thyroid Disorders. Radiation Dosimetry of Diagnostic Procedures. Radiation Safety Procedures for High-Level I-131 Therapies. X-Ray Fluorescent Scanning. Thyroid Sonography. Computed Tomography in Thyroid Disease. Magnetic Resonance Imaging in Thyroid Disease. Parathyroid Imaging.
Sandler, M.P.; Patton, J.A.; Partain, C.L.
The histone methyltransferase EZH2, an oncogene common to benign and malignant parathyroid tumors.
Primary hyperparathyroidism (pHPT) resulting from parathyroid tumors is a common endocrine disorder with incompletely understood etiology. In renal failure, secondary hyperparathyroidism (sHPT) occurs with multiple tumor development as a result of calcium and vitamin D regulatory disturbance. The aim of this study was to investigate a potential role of the histone 3 lysine 27 methyltransferase EZH2 in parathyroid tumorigenesis. Parathyroid tumors from patients with pHPT included adenomas and carcinomas. Hyperplastic parathyroid glands from patients with HPT secondary to uremia and normal parathyroid tissue specimens were included in this study. Quantitative RT-PCR, western blotting, bisulfite pyrosequencing, colony formation assay, and RNA interference were used. EZH2 was overexpressed in a subset of the benign and in all malignant parathyroid tumors as determined by quantitative RT-PCR and western blotting analyses. Overexpression was explained by EZH2 gene amplification in a large fraction of tumors. EZH2 depletion by RNA interference inhibited sHPT-1 parathyroid cell line proliferation as determined by tritium-thymidine incorporation and colony formation assays. EZH2 depletion also interfered with the Wnt/?-catenin signaling pathway by increased expression of growth-suppressive AXIN2, a negative regulator of ?-catenin stability. Indeed, EZH2 contributed to the total level of aberrantly accumulated transcriptionally active (nonphosphoylated) ?-catenin in the parathyroid tumor cells. To our knowledge EZH2 gene amplification presents the first genetic aberration common to parathyroid adenomas, secondary hyperplastic parathyroid glands, and parathyroid carcinomas. This supports the possibility of a common pathway in parathyroid tumor development. PMID:24292603
Svedlund, Jessica; Barazeghi, Elham; St�lberg, Peter; Hellman, Per; �kerstr�m, G�ran; Bj�rklund, Peyman; Westin, Gunnar
Summary Although progress is being made in the development of new clinical treatments for traumatic brain injury (TBI), little is known about whether such treatments are effective in older patients, in whom frailty, prior medical conditions, altered metabolism, and changing sensitivity to medications all can affect outcomes following a brain injury. In this review we consider TBI to be a complex, highly variable, and systemic disorder that may require a new pharmacotherapeutic approach, one using combinations or cocktails of drugs to treat the many components of the injury cascade. We review some recent research on the role of vitamin D hormone and vitamin D deficiency in older subjects, and on the interactions of these factors with progesterone, the only treatment for TBI that has shown clinical effectiveness. Progesterone is now in phase III multicenter trial testing in the United States. We also discuss some of the potential mechanisms and pathways through which the combination of hormones may work, singly and in synergy, to enhance survival and recovery after TBI. PMID:20129500
Cekic, Milos; Stein, Donald G.
Vitamin d status in irish children and adolescents: value of fortification and supplementation.
Background. Vitamin D has important skeletal and extraskeletal roles but those living at northerly latitudes are at risk of suboptimal levels because of reduced sunlight exposure. Aim. To describe the vitamin D status of Irish children and identify factors predictive of vitamin D status. Methods. A prospective cross sectional study was undertaken over a 12 month period. Two hundred and fifty two healthy children attending for minor medical or surgical procedures were recruited. All had 25-hydroxyvitamin D (25OHD), parathyroid hormone and bone profiles measured. Results. The mean (standard deviation) for 25OHD was 51(25) nmol/L (20.4 (10) ng/mL). Forty-five percent had levels >50 nmol/L (20 ng/mL). The following variables were significantly associated with 25OHD levels >50 nmol/L (20 ng/mL): sample drawn in April-September, use of vitamin D supplements, consumption of formula milk, and non-African ethnicity. Conclusion. More than half of the children in this study had 25OHD levels less than 50 nmol/L (20 ng/mL). Vitamin D status was significantly improved by augmented oral vitamin D intake. PMID:25006113
Carroll, Aoife; Onwuneme, Chike; McKenna, Malachi J; Mayne, Philip D; Molloy, Eleanor J; Murphy, Nuala P
Core binding factor beta (Cbf?) is essential for embryonic bone morphogenesis. Yet the mechanisms by which Cbf? regulates chondrocyte proliferation and differentiation as well as postnatal cartilage and bone formation remain unclear. Hence, using paired-related homeobox transcription factor 1-Cre (Prx1-Cre) mice, mesenchymal stem cell-specific Cbf?-deficient (Cbf?(f/f) Prx1-Cre) mice were generated to study the role of Cbf? in postnatal cartilage and bone development. These mutant mice survived to adulthood but exhibited severe sternum and limb malformations. Sternum ossification was largely delayed in the Cbf?(f/f) Prx1-Cre mice and the xiphoid process was noncalcified and enlarged. In newborn and 7-day-old Cbf?(f/f) Prx1-Cre mice, the resting zone was dramatically elongated, the proliferation zone and hypertrophic zone of the growth plates were drastically shortened and disorganized, and trabecular bone formation was reduced. Moreover, in 1-month-old Cbf?(f/f) Prx1-Cre mice, the growth plates were severely deformed and trabecular bone was almost absent. In addition, Cbf? deficiency impaired intramembranous bone formation both in vivo and in vitro. Interestingly, although the expression of Indian hedgehog (Ihh) was largely reduced, the expression of parathyroid hormone-related protein (PTHrP) receptor (PPR) was dramatically increased in the Cbf?(f/f) Prx1-Cre growth plate, indicating that that Cbf? deficiency disrupted the Ihh-PTHrP negative regulatory loop. Chromatin immunoprecipitation (ChIP) analysis and promoter luciferase assay demonstrated that the Runx/Cbf? complex binds putative Runx-binding sites of the Ihh promoter regions, and also the Runx/Cbf? complex directly upregulates Ihh expression at the transcriptional level. Consistently, the expressions of Ihh target genes, including CyclinD1, Ptc, and Pthlh, were downregulated in Cbf?-deficient chondrocytes. Taken together, our study reveals not only that Cbf? is essential for chondrocyte proliferation and differentiation for the growth and maintenance of the skeleton in postnatal mice, but also that it functions in upregulating Ihh expression to promoter chondrocyte proliferation and osteoblast differentiation, and inhibiting PPR expression to enhance chondrocyte differentiation. PMID:24821091
Tian, Fei; Wu, Mengrui; Deng, Lianfu; Zhu, Guochun; Ma, Junqing; Gao, Bo; Wang, Lin; Li, Yi-Ping; Chen, Wei
Prior studies showed conflicting results regarding the association between 25-hydroxyvitamin D (25(OH)D) levels and mineral metabolism in end-stage renal disease. In order to determine whether the bioavailable vitamin D (that fraction not bound to vitamin D-binding protein) associates more strongly with measures of mineral metabolism than total levels, we identified 94 patients with previously measured 25(OH)D and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) from a cohort of incident hemodialysis patients. Vitamin D-binding protein was measured from stored serum samples. Bioavailable 25(OH)D and 1,25(OH)(2)D were determined using previously validated formulae. Associations with demographic factors and measures of mineral metabolism were examined. When compared with whites, black patients had lower levels of total, but not bioavailable, 25(OH)D. Bioavailable, but not total, 25(OH)D and 1,25(OH)(2)D were each significantly correlated with serum calcium. In univariate and multivariate regression analysis, only bioavailable 25(OH)D was significantly associated with parathyroid hormone levels. Hence, bioavailable vitamin D levels are better correlated with measures of mineral metabolism than total levels in patients on hemodialysis. PMID:22398410
Bhan, Ishir; Powe, Camille E; Berg, Anders H; Ankers, Elizabeth; Wenger, Julia B; Karumanchi, S Ananth; Thadhani, Ravi I
Parathyroid ultrastructure after aldehyde fixation, high-pressure freezing, or microwave irradiation
Parathyroid cell variants, commonly observed in parathyroid glands fixed by immersion in glutaraldehyde, are believed to be the result of cyclic changes in the course of parathyroid hormone secretion. Immersion of bovine parathyroid glands in a mixture consisting of 1% glutaraldehyde, 1.5% formaldehyde, and 2.5% acrolein, followed by post-fixation in 1% osmium tetroxide, resulted in high uniformity with only one cell variant, whereas the same fixation procedure led to disruption of cell membranes and formation of cell variants in rat parathyroids. Parathyroid glands of both cattle and rats prepared by high-pressure quick-freezing and subsequent freeze-substitution contained only one cell variant. Excellent preservation of the ultrastructure of bovine and rat parathyroids, also exhibiting only one cell variant, was achieved by microwave irradiation in the presence of 2.5% glutaraldehyde in Na-cacodylate followed by post-fixation with OsO4 in Na-cacodylate or s-collidine, both containing Ca2+ and Mg2+. Use of the appropriate buffer, as well as osmication, is essential for successful fixation utilizing microwave energy. The main effects are considered to be heating specimens within sufficient short periods and enhancement of subsequent osmium fixation. The results support the idea, arising after examination of perfusion-fixed parathyroid tissue, that parathyroid cell variants occur during improper aldehyde fixation rather than that they express functional diversity.
Marti, R.; Wild, P.; Schraner, E.M.; Mueller, M.; Moor, H.
Vitamin K Status in Relation to Bone Metabolism in Patients with Renal Failure
Vitamin K abnormalities may be involved in the pathogenesis of bone disease in patients with advanced renal failure since vitamin K plays a role in the synthesis of osteocalcin, a marker of bone formation. Vitamin K may also indirectly suppress parathyroid function. The aim of this study was to evaluate vitamin K status in patients with renal failure and in
The kidney is essential for the maintenance of normal calcium and phosphorus homeostasis. Calcium and inorganic phosphorus are filtered at the glomerulus, and are reabsorbed from tubular segments by transporters and channels which are regulated by 1?,25-dihydroxyvitamin (1?,25(OH)2D) and parathyroid hormone (PTH). The kidney is the major site of the synthesis of 1?,25(OH)2D under physiologic conditions, and is one of the sites of 24,25-dihydroxyvitamin D (24,25(OH)2D) synthesis. The activity of the 25(OH)D-1?-hydroxylase, the mixed function oxidase responsible for the synthesis of 1?,25(OH)2D, is regulated by PTH, 1?,25(OH)2D, fibroblast growth factor 23 (FGF23), inorganic phosphorus and other growth factors. Additionally, the vitamin D receptor which binds to, and mediates the activity of 1?,25(OH)2D, is widely distributed in the kidney. Thus, the kidney by regulating multiple transport and synthetic processes is indispensible in the maintenance of mineral homeostasis in physiological states. PMID:22426203
Kumar, Rajiv; Tebben, Peter J.; Thompson, James R.
Vitamin D deficiency in the elderly in Athens, Greece.
Vitamin D deficiency characterized by low 25-hydroxyvitamin D [25(OH)D] levels has been found to be prevalent among the elderly in many regions of the world. To investigate the vitamin status in elderly community-living persons in Athens, we measured 25(OH)D and parathyroid hormone (PTH) in elderly persons and young blood donors during the winter and summer. The changes in these parameters in a subgroup of the elderly were studied longitudinally. The blood donors had mean 25(OH)D levels similar in winter and summer and twice as high in winter compared to the elderly. At the end of the winter, about 20% of the elderly had severe vitamin D deficiency, with 25(OH)D below 25 nmol/l, and only 6.5% could be judged as vitamin D sufficient with values above 80 nmol/l. The situation improved during summer, although 64.8% of the elderly continued to have levels below 80 nmol/l. Mean plasma PTH in the elderly in summer was not different from that of blood donors; however, it was doubled during the winter. Regression of PTH on 25(OH)D demonstrated that PTH starts to rise when 25(OH)D falls below approximately 80 nmol/l. We conclude that severe vitamin deficiency associated with secondary hyperparathyroidism is not uncommon in the elderly in Athens during the winter; it subsides during summer, although only one-third of the elderly population attain vitamin D sufficiency during summer. We found that a threshold value of 25(OH)D exists at approximately 80 nmol/l, below which secondary hyperparathyroidism ensues, as described previously. PMID:17447119
Papapetrou, Peter D; Triantaphyllopoulou, Maria; Karga, Helen; Zagarelos, Panagiotis; Aloumanis, Kyriakos; Kostakioti, Eleni; Vaiopoulos, George
Top-trophic predators like California sea lions bioaccumulate high levels of persistent fat-soluble pollutants that may provoke physiological impairments such as endocrine or vitamins A and E disruption. We measured circulating levels of polychlorinated biphenyls (PCBs) and dichlorodiphenyltrichloroethane (DDT) in 12 healthy juvenile California sea lions captured on A�o Nuevo Island, California, in 2002. We investigated the relationship between the contamination
Cathy Debier; Gina M. Ylitalo; Michael Weise; Frances Gulland; Daniel P. Costa; Burney J. Le Boeuf; Tanguy de Tillesse; Yvan Larondelle
Enhanced Excretion of Vitamin D Binding Protein in Type 1 Diabetes: A Role in Vitamin D Deficiency?
Context: Vitamin D deficiency is an increasingly recognized comorbidity in patients with both type 1 (T1D) and type 2 diabetes, particularly associated with the presence of diabetic nephropathy. Objective: Because we have previously reported enhanced excretion of megalin in the urine of T1D patients with microalbuminuria, we hypothesized that concurrent urinary loss of the megalin ligand, vitamin D binding protein, might contribute mechanistically to vitamin D deficiency. Design and Participants: Examining a study cohort of 115 subjects with T1D, aged 14�40 yr, along with 55 age-matched healthy control subjects, we measured plasma and urine concentrations of vitamin D binding protein (VDBP) along with serum concentrations of total calcium, parathyroid hormone, 25-hydroxyvitamin D, and 1, 25-dihydroxyvitamin D; these results were compared between groups and investigated for relationships with metabolic control status or with albuminuria. Main Outcome Measure: Between-group differences in urinary VDBP concentration were the main outcome measures. Results: A marked increase in the urinary excretion of VDBP was apparent in subjects with T1D, compared with control subjects. Using multivariate regression modeling, significant correlates of urinary VDBP excretion included microalbuminuria (P = 0.004), glycosylated hemoglobin (P = 0.010), continuous glucose monitoring system average capillary glucose (P = 0.047), and serum 1,25(OH)2D concentrations (P = 0.037). Vitamin D deficiency or insufficiency was slightly more prevalent in diabetic subjects with albuminuria, coincident with the increase in urine VDBP excretion. Conclusions: These findings suggest that, theoretically, exaggerated urinary loss of VDBP in T1D, particularly in persons with albuminuria, could contribute mechanistically to vitamin D deficiency in this disease. PMID:20943786
Thrailkill, Kathryn M.; Jo, Chan-Hee; Cockrell, Gael E.; Moreau, Cynthia S.; Fowlkes, John L.
Background. Parathyroid surgery for sporadic primary hyperparathyroidism (pHPT) can be accomplished with local\\/regional anesthesia and intraoperative monitoring of intact parathyroid hormone without exclusion criteria through a 1.0- to 1.25-inch (2.5- to 3.2-cm) incision (MIPL) in a high proportion of patients. Methods. One hundred thirty-one consecutive patients with pHPT were offered MIPL. One hundred three patients elected to have this procedure.
Jack M Monchik; Leonardo Barellini; Peter Langer; Arif Kahya
An unusual case of brown tumor of hyperparathyroidism associated with ectopic parathyroid adenoma
Brown tumor is a giant cell lesion associated with hyperparathyroidism. It is a non-neoplastic condition and represents terminal stage of the remodeling process in hyperparathyroid state. We report a case of brown tumor with multiple lesions in craniofacial region associated with ectopic parathyroid adenoma revealed after acute L-thyroxine poisoning. This case report emphasizes on the need for routine biochemical investigations along with serum calcium, phosphorus and parathyroid hormone levels in patients on thyroxine therapy. PMID:24932128
Mohan, Mathan; Neelakandan, Ravana Sundaram; Siddharth, D.; Sharma, Ravi
Randomised controlled trial of vitamin D supplementation in sarcoidosis
Objectives The role vitamin D intake/production plays in sarcoidosis-associated hypercalcaemia is uncertain. However, authoritative reviews have recommended avoiding sunlight exposure and vitamin D supplements, which might lead to adverse skeletal outcomes from vitamin D insufficiency. We investigated the effects of vitamin D supplementation on surrogate measures of skeletal health in patients with sarcoidosis and vitamin D insufficiency. Design Randomised, placebo-controlled trial. Setting Clinical research centre. Participants 27 normocalcaemic patients with sarcoidosis and 25-hydroxyvitamin D (25OHD) <50?nmol/L. Intervention 50?000?IU weekly cholecalciferol for 4?weeks, then 50?000?IU monthly for 11?months or placebo. Primary and secondary outcome measures The primary endpoint was the change in serum calcium over 12?months, and secondary endpoints included measurements of calcitropic hormones, bone turnover markers and bone mineral density (BMD). Results The mean age of participants was 57?years and 70% were women. The mean (SD) screening 25OHD was 35 (12) and 38 (9) nmol/L in the treatment and control groups, respectively. Vitamin D supplementation increased 25OHD to 94?nmol/L after 4?weeks, 84?nmol/L at 6?months and 78?nmol/L at 12?months, while levels remained stable in the control group. 1,25-Dihydroxy vitamin D levels were significantly different between the groups at 4?weeks, but not at 6 or 12?months. There were no between-groups differences in albumin-adjusted serum calcium, 24?h urine calcium, markers of bone turnover, parathyroid hormone or BMD over the trial. One participant developed significant hypercalcaemia after 6?weeks (total cholecalciferol dose 250?000?IU). Conclusions In patients with sarcoidosis and 25OHD <50?nmol/L, vitamin D supplements did not alter average serum calcium or urine calcium, but had no benefit on surrogate markers of skeletal health and caused one case of significant hypercalcaemia. Trial registration This trial is registered at the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au). The registration number is ACTRN12607000364471, date of registration 5/7/2007. PMID:24157819
Bolland, Mark J; Wilsher, Margaret L; Grey, Andrew; Horne, Anne M; Fenwick, Sheryl; Gamble, Greg D; Reid, Ian R
All the Parathyroids, All the Time: The Parathyroids, Basic and Clinical Concepts
NASA Technical Reports Server (NTRS)
The second edition of The Parathyroids, Basic and Clinical Concepts is a comprehensive source of information that most endocrinologists will want to have on their bookshelves. Not only does it describe the basic physiology of the parathyroids, but also the clinical aspects of hyper- and hypoparathyroid states. The authors have retained the general organization of the first edition but have updated and revised all the sections and added a few new chapters. The list of authors is impressive, comprising the many students of G. Auerbach, whose laboratory isolated the hormone and whose untimely death ten years ago inspired the first edition of the book. The younger generation of scientists from several other laboratories, who have made significant contributions to parathyroid physiology and molecular genetics, are also included. Chapters about the presentation of clinical primary hyperparathyroidism in Europe, India, Brazil and China are of particular interest. Classic features of the disease are found that contrast with the often asymptomatic disease found in the West, which is discovered through modest increases in serum calcium from biochemical screening.
Arnaud, Sara B.
Vitamin D, disease and therapeutic opportunities
The discovery of the vitamin D endocrine system and a receptor for the hormonal form, 1?,25-dihydroxyvitamin D3, has brought a new understanding of the relationship between vitamin D and metabolic bone diseases, and has also established the functions of vitamin D beyond the skeleton. This has ushered in many investigations into the possible roles of vitamin D in autoimmune diseases,
Lori A. Plum; Hector F. DeLuca
This cross-sectional study assessed vitamin D status of healthy infants and young children undergoing routine care in a medical center pediatric clinic in Sacramento, CA, and evaluated associations of status with markers of vitamin D function. Such data have not recently been reported from similar locations with sunny climates that should minimize risk of deficiency. Exposures included diet, supplement use, and sun exposure, and outcomes included plasma 25-hydroxy vitamin D (25[OH]D), parathyroid hormone (PTH), bone-specific alkaline phosphatase, and eight markers of immune activation. The median age of the 173 subjects was 12 months (range, 6-19); 49% were female. The median 25(OH)D was 85 nmol/l (range, 9-198); five subjects (2.9%) had <27.5 nmol/l, indicative of deficiency; 14 (8.1%) had <50 nmol/l, and 49 (28.3%) had <75 nmol/l. Most subjects (154; 89%) received some vitamin-D-fortified cow's milk or formula while 19 (11%) received breast milk as the only milk source. Breastfeeding was associated with risk of vitamin D deficiency (p < 0.001). Subjects with 25(OH)D <27.5 nmol/l had elevated PTH (p = 0.007). Only four of 35 breastfed infants (11%) consuming <500 ml/day vitamin-D-fortified formula or milk received vitamin D supplements. Plasma interleukin (IL)-1? was significantly higher (p = 0.036) in infants in the highest vs. lowest 25(OH)D decile. In conclusion, this study demonstrates that vitamin D deficiency with elevated PTH remains a risk for breastfed subjects not receiving supplemental vitamin D even in a region with a sunny, temperate climate. Strategies to improve supplementation should be sought. PMID:20532799
Liang, Lisa; Chantry, Caroline; Styne, Dennis M; Stephensen, Charles B
Patterns in the Parathyroid Response to Sodium Bicarbonate Infusion Test in Healthy Volunteers
Background. The sodium bicarbonate infusion test evaluates the function of the parathyroid glands. The present study aims to evaluate the range of parathyroid response in healthy individuals and the potential influence of various factors. Methods. Fifty healthy volunteers were subjected to the test. Levels of vitamin D, calcium, albumin, and PTH were measured before infusion. PTH was measured at 3, 5, 10, 30, and 60 minutes after infusion. Results. A curve describing the response of parathyroids to the test was drawn. Twenty percent of the subjects had blunted PTH response. No significant difference was observed between normal and blunted responders concerning age, BMI, baseline PTH, or calcium levels. Nonetheless, there was a significant difference in vitamin D levels (P = 0.024). Interpretation. The test is easy to perform and may be used for everyday screening. It has to be clarified whether our observations are, at least partly, produced due to the presence of individuals with a constitutively blunted response or if low levels of vitamin D decrease the ability of the parathyroids to respond. Whichever the case, PTH response of normal individuals to sodium bicarbonate infusion test is more varied than previously thought and vitamin D levels influence it. PMID:24804234
Papavramidis, Theodossis S.; Anastasiou, Olympia E.; Pliakos, Ioannis; Triantafyllopoulou, Konstantina; Kokaraki, Georgia; Papavramidis, Spiros
Vitamin D is an essential steroid hormone, with well-established effects on mineral metabolism, skeletal health, and recently established effects on the cardiovascular and immune systems. Vitamin D deficiency is highly prevalent and evidence is mounting that it contributes to the morbidity and mortality of multiple chronic diseases, including systemic lupus erythematosus (SLE). Patients with SLE avoid the sun because of photosensitive rashes and potential for disease flare, so adequate oral supplementation is critical. This review will describe the prevalence of vitamin D deficiency in patients with SLE, identify risk factors for deficiency, describe the consequences of deficiency, and review current vitamin D recommendations for patients with rheumatic diseases. PMID:20969555
Kamen, Diane L.
Osteoblast-specific expression of the bone protein osteocalcin is controlled at the transcriptional level by the steroid hormone 1{alpha},25-dihydroxyvitamin D{sub 3}. As this protein may represent a marker for bone activity in human disease, the authors examined the regulation of its expression at the molecular level by evaluating human osteocalcin gene promoter function. They describe regions within the promoter that contribute to basal expression of the gene in osteoblast-like cells in culture. Further, they define a 21-base-pair DNA element with the sequence 5{prime}-GTGACTCACCGGGTGAACGGG-3{prime}, which acts in cis to mediate 1{alpha},25-dihydroxyvitamin D{sub 3} inducibility of the osteocalcin gene. This response element bears sequence similarity with other short DNA segments, particularly those for estrogen and thyroid hormone, which act together with their respective trans-acting receptors to modulate gene transcription.
Kerner, S.A.; Scott, R.A.; Pike, J.W. (Baylor College of Medicine, Houston, TX (USA))
Parathyroid adenoma in third pharyngeal pouch cyst as a rare case of primary hyperparathyroidism.
The primitive thymus and inferior parathyroid derive from the third branchial cleft. During embryonic development, these structures descend, reaching their final localisation. Third branchial cleft anomalies present usually as a fistula, abscess or cyst. However, there are no reports on parathyroid adenomas in the literature other than as a morphological possibility. We describe the case of a 47-year-old man, who had been diagnosed with arterial hypertension and who presented with a cervical mass at the edge of the lower third of the sternocleidomastoid muscle. On ultrasonography, the mass had a cystic walled appearance. Laboratory analysis only revealed an intact parathyroid hormone level of 140.5pg/ml. Sestamibi imaging showed a probable parathyroid adenoma in the anterior mediastinum. During surgery, a tract running from beyond the superior thyroid pedicle to the superior mediastinum was dissected and removed. In the inferior end of the tract, a brown mass was visible. Pathological examination revealed a thymus cyst surrounding a parathyroid adenoma. The primal alteration was the lack of division between the thymus and inferior parathyroid gland, and the prompt prevention of their development. In the case of our patient, a parathyroid adenoma had grown by chance. PMID:25245714
Salido, S; G�mez-Ram�rez, J; Bravo, Jm; Mart�n-P�rez, E; Fern�ndez-D�az, G; Nova, Jl M��oz de; Auza, J; Larra�aga, E
Background The study was conducted to estimate the effect of depot medroxyprogesterone acetate (DMPA) and oral contraceptives (OC) containing 20 mcg ethinyl estradiol on serum B12 and whether observed changes impact bone mineral density (BMD). Study Design Serum B12 and BMD at the lumbar spine and femoral neck were measured on 703 women using OC, DMPA, or nonhormonal (NH) birth control at baseline and every 6 months thereafter for 3 years. Results OC and DMPA users experienced greater decreases in B12 than NH users (p<.001). A sharp decrease in B12 was observed during the first 6 months of hormonal contraceptive use (OC: 97 pg/mL and DMPA: 64 pg/mL) in contrast to 14 pg/mL among NH users (20%, 13% and 3% of their baseline values, respectively). Over the following 30 months, B12 levels of OC users remained almost flat while DMPA users had a further 22 units decrease. Very few women demonstrated B12 deficiency. Moreover, B12 levels were not associated with BMD. Conclusion Hormonal contraception causes B12 levels to decrease, but this does not appear to be clinically significant or affect BMD. PMID:22464408
Berenson, Abbey B.; Rahman, Mahbubur
Hormonal growth control of cells in culture
Summary��Serum is the last undefined component in cell culture media. Our results indicate that the primary role of serum is to provide\\u000a hormones and that serum can be replaced by a group of hormones. A rat pituitary cell line, GH3, can grow in serum-free medium if the medium is supplemented with 3,3?,5-triiodothyronine, TSH-releasing hormone, transferrin,\\u000a parathyroid hormone, insulin and three
I. Hayashi; J. Larner; G. Sato
Background The aim of this study was to explore a new method to identify and protect parathyroid glands in neck lymph node dissection for patients with thyroid cancer. Material/Methods One hundred patients with thyroid cancer underwent total thyroidectomy combined with central neck lymph node dissection. During the operation, 50 patients receiving nano-carbon suspension were included in the experiment group, and 50 patients without nano-carbon suspension were included in the control group. We compared changes in parathyroid hormone levels before surgery and at 48 h after surgery between the 2 groups and of serum Ca2+ level within 48 h after surgery, as well as postoperative parathyroid pathological and lymph node dissection results. Results Eight and 1 parathyroid glands were detected pathologically in the control and experimental group, respectively. Decrease in parathyroid hormone level at 48 h occurred in 7 patients in the control group and 1 patient in the experimental group. Hypocalcemia was found at 48 h after surgery in 10 patients in the control group and 2 patients in the experimental group. Conclusions Nano-carbon suspension can cause development of the thyroid gland and the central lymph node and a negative development of parathyroid glands. Careful identification and removal of black-stained lymphatic tissues in the process of total thyroidectomy with neck lymph node dissection can ensure a complete lymph node dissection and prevent parathyroid damage, thus effectively reducing the incidence of hypoparathyroidism. PMID:25311844
Tian, Wuguo; Jiang, Yan; Gao, Bo; Zhang, Xiaohua; Zhang, Shu; Zhao, Jianjie; He, Yujun; Luo, Donglin
A 47-year-old man presented with multiple lung metastases from parathyroid carcinoma that caused hyperparathyroidism and refractory hypercalcemia. Lung radiofrequency (RF) ablation was repeated to decrease the serum calcium and parathyroid hormone levels and improve general fatigue. Pulmonary resection was combined for lung hilum metastases. The patient is still alive 4 years after the initial RF session. He has received 20 RF sessions for 50 lung metastases during this period.
Tochio, Maki, E-mail: email@example.com; Takaki, Haruyuki; Yamakado, Koichiro; Uraki, Junji; Kashima, Masataka; Nakatsuka, Atsuhiro [Mie University School of Medicine, Department of Radiology (Japan); Takao, Motoshi; Shimamoto, Akira; Tarukawa, Tomohito; Shimpo, Hideto [Mie University School of Medicine, Department of Thoracic and Cardiovascular Surgery (Japan); Takeda, Kan [Mie University School of Medicine, Department of Radiology (Japan)
Vitamin D Bioavailability and Catabolism in Pediatric Chronic Kidney Disease
Background Vitamin D-binding protein (DBP) and catabolism have not been examined in childhood chronic kidney disease (CKD). Methods Serum vitamin D [25(OH)D, 1,25(OH)2D, 24,25(OH)2D], DBP, intact parathyroid hormone (iPTH), and fibroblast growth factor-23 (FGF23) concentrations were measured in 148 participants with CKD stages 2�5D secondary to congenital anomalies of the kidney/urinary tract (CAKUT), glomerulonephritis (GN), or focal segmental glomerulosclerosis (FSGS). Free and bioavailable 25(OH)D were calculated using total 25(OH)D, albumin and DBP. Results All vitamin D metabolites were lower with more advanced CKD (p<0.001) and glomerular diagnoses (p?0.002). Among non-dialysis participants, DBP was lower in FSGS vs. other diagnoses (FSGS-dialysis interaction p=0.02). Winter season, older age, FSGS and GN, and higher FGF23 were independently associated with lower free and bioavailable 25(OH)D. Black race was associated with lower total 25(OH)D and DBP, but not free or bioavailable 25(OH)D. 24,25(OH)2D was the vitamin D metabolite most strongly associated with iPTH. Lower 25(OH)D, black race, greater CKD severity, and higher iPTH were independently associated with lower 24,25(OH)2D, while higher FGF23 and GN were associated with greater 24,25(OH)2D. Conclusions Children with CKD exhibit altered catabolism and concentrations of DBP and free and bioavailable 25(OH)D, and there is an important impact of their underlying disease. PMID:23728936
Denburg, Michelle R.; Kalkwarf, Heidi J.; de Boer, Ian H.; Hewison, Martin; Shults, Justine; Zemel, Babette S.; Stokes, David; Foerster, Debbie; Laskin, Benjamin; Ramirez, Anthony; Leonard, Mary B.
Vitamin D Status in Healthy Omani Women of Childbearing Age
Objectives: Sunlight exposure has a vital role in vitamin D synthesis. Although vitamin D deficiency has been well documented in temperate zones, studies have been scarce in tropical countries where the population is well covered and for various reasons avoids sun exposure. The objective of this study was to investigate serum 25-hydroxyvitamin D [25(OH)D] levels and its relationship to biochemical bone profile, exposure to sunlight and vitamin D intake amongst Omani women of childbearing age. Methods: 41 apparently healthy women working at the Royal Hospital, Muscat, Oman and aged 18�45 years, with mean � SD of 29 � 6 years, were included in this study conducted in December 2006. They completed a questionnaire regarding the duration of sun exposure, food intake and type of clothing worn. Blood samples were collected from them and analysed for serum 25(OH)D, calcium, phosphate, alkaline phosphatise and parathyroid hormone levels. Results: All the women had a 25(OH)D level <50 nmol/L as the cut-off for deficiency. 25(OH)D levels were strongly correlated with the lack of sun exposure (r = 0.672, P < 0.001) and a significant correlation was also found between 25(OH) D level and food intake (r = 0.482, P < 0.01). Conclusion: Subclinical 25(OH)D deficiency may be prevalent amongst Omani women. Risk factors such as poor sunlight exposure should be addressed in women of childbearing age and, if increased sunlight exposure is not possible, oral supplementation should be considered to avoid all the consequence and complications of vitamin D deficiency. PMID:21509209
Al-Kindi, Manal K
Prevalence of hypovitaminosis D and predictors of vitamin D status in Italian healthy adolescents
Background Vitamin D plays an important role in health promotion during adolescence. Vitamin D deficiency and insufficiency are common in adolescents worldwide. Few data on vitamin D status and risk factors for hypovitaminosis D in Italian adolescents are currently available. Methods 25-hydroxyvitamin D (25-OH-D) and parathyroid hormone (PTH) levels were evaluated in 427 Italian healthy adolescents (10.0-21.0�years). We used the following cut-off of 25-OH-D to define vitamin D status: deficiency?50�nmol/L; insufficiency 50-75�nmol/L; sufficiency???75�nmol/L. Hypovitaminosis D was defined as 25-OH-D levels?75.0�nmol/L and severe vitamin D deficiency as 25-OH-D levels?25.0�nmol/L. We evaluated gender, residence, season of blood withdrawal, ethnicity, weight status, sun exposure, use of sunscreens, outdoor physical activity, and history of fractures as predictors of vitamin D status. Results Enrolled adolescents had a median serum 25-OH-D level of 50.0�nmol/L, range 8.1-174.7, with 82.2% having hypovitaminosis D. Vitamin D deficiency and insufficiency were detected in 49.9% and 32.3% of adolescents, respectively. Among those with deficiency, 38 subjects were severely deficient (38/427, 8.9% of the entire sample). Non-white adolescents had a higher prevalence of severe vitamin D deficiency than white subjects (6/17-35.3% vs 32/410-7.8% respectively, p?=?0.002). Logistic regression showed increased risk of hypovitaminosis D as follows: blood withdrawal taken in winter-spring (Odds ratio (OR) 5.64) compared to summer-fall period; overweight-obese adolescents (OR 3.89) compared to subjects with normal body mass index (BMI); low sun exposure (OR 5.94) compared to moderate-good exposure and regular use of sunscreens (OR 5.89) compared to non regular use. Adolescents who performed?3�hours/week of outdoor exercise had higher prevalence of hypovitaminosis D. Gender, residence, and history of fractures were not associated with vitamin D status. Serum 25-OH-D levels were inversely related to PTH (r?=?-0.387, p?0.0001) and BMI-SDS (r?=?-0.141, p?=?0.007). 44/427 (10.3%) adolescents showed secondary hyperparathyroidism. Conclusions Italian adolescents have high prevalence of vitamin D deficiency and insufficiency. Pediatricians should tackle predictors of vitamin D status, favoring a healthier lifestyle and promoting supplementation in the groups at higher risk of hypovitaminosis D. PMID:24902694
Synchronous parathyroid adenoma and thyroid papillary carcinoma: a case report
A 51-year-old female patient presented with atypical chest pain, laryngo-oesophageal reflux, increased levels of serum calcium and parathyroid hormone. Ultrasonography showed a multinodular goiter with a prominent solid nodule in the lower left thyroid lobe and a solid hypoechoic nodule outside this area. Tc99m-sestamibi parathyroid scintigraphy was performed to investigate a primary hyperparathyroidism, revealing an area with increased uptake in the lower left thyroid lobe and another area with marked uptake lower than this level. Thyroid scintigraphy with 99mTc showed a cold nodule of the left lower pole. FNA of the thyroid nodule was positive for papillary carcinoma later verified by postoperative histopathology. This case underlines the need for a clinical high index of suspicion for synchronous hyperparathyroidism and thyroid cancer. PMID:20062698
Synchronous parathyroid adenoma and thyroid papillary carcinoma: a case report.
A 51-year-old female patient presented with atypical chest pain, laryngo-oesophageal reflux, increased levels of serum calcium and parathyroid hormone. Ultrasonography showed a multinodular goiter with a prominent solid nodule in the lower left thyroid lobe and a solid hypoechoic nodule outside this area.Tc99m-sestamibi parathyroid scintigraphy was performed to investigate a primary hyperparathyroidism, revealing an area with increased uptake in the lower left thyroid lobe and another area with marked uptake lower than this level. Thyroid scintigraphy with 99mTc showed a cold nodule of the left lower pole. FNA of the thyroid nodule was positive for papillary carcinoma later verified by postoperative histopathology.This case underlines the need for a clinical high index of suspicion for synchronous hyperparathyroidism and thyroid cancer. PMID:20062698
Iakovou, Ioannis P; Konstantinidis, Iordanis E; Chrisoulidou, Alexandra I; Doumas, Argyrios S
Vitamin D - Dependent Rickets, Type II Case Report
Aim: The aim of this work the report of one case with vitamin D-dependent rickets, type II. Methods: Diagnosis has been established based on anamnesis, physical examination, laboratory findings and radiological examination. Results: A female child (age 25 months) has been hospitalized due to bone deformity, bone pain, alopecia and walking difficulties. The laboratory findings have revealed that the calcium values was low (1.20 mmol/L), phosphates in the reference value (1.30 mmol/L) the alkaline phosphatase value was quite high (852 IU/L), high value of parathyroid hormone (9.21 pmol/L), normal value of 25- hydroxyvitamin D, whereas the values of 1,25-dihydroxyvitamin D was high (185 ?mol/L). Radiographic changes were evident and typical in the distal metaphysis of radius and ulna as well as in the bones of lower limbs (distal metaphysis of femur and proximal metaphysis of tibia and fibula). After treatment with calcium and calcitriol, the above mentioned clinical manifestations, laboratory test values and the radiographic changes in bones withdrew. Conclusions: Vitamin D-dependent rickets, type II is a rare genetic recessive disease, and its treatment includes a constant use of calcium and calcitriol. PMID:24757409
Azemi, Mehmedali; Berisha, Majlinda; Ismaili-Jaha, Vlora; Kolgeci, Selim; Hoxha, Rina; Grajcevci-Uka, Violeta; Hoxha-Kamberi, Teuta
Vitamin D status and risk of ischemic stroke in North Indian patients
Context: Accumulating evidence suggests that vitamin D deficiency is associated with increased risk of stroke. Contributing mechanisms have been linked to the association of vitamin D deficiency with the presence of hypertension, diabetes mellitus, and atherosclerosis, however, the evidence is conflicting. Aims: This study sought to determine the association of vitamin D deficiency with ischemic stroke and its risk factors. Settings and Design: Cross-sectional case control study. Subjects and Methods: We measured serum 25-hydroxyvitamin D [25(OH) D] and intact parathyroid hormone (iPTH) levels in 73 patients of ischemic stroke, presenting within 7 days of onset of stroke and compared with 70 age and gender matched controls. Statistical Analysis Used: The statistical analysis was carried out using Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, version 17.0 for Windows). Results: The mean age of patients and controls was 59.9 � 11.2 years and 57.9 � 9.7 years, respectively (P = 0.26). Of 67.1% patients were men as compared to 65.7% controls (P = 0.86). There was no significant difference in the prevalence of vitamin D deficiency/insufficiency (P = 0.25), mean 25(OH) D levels (P = 0.75), and iPTH levels (P = 0.10) between cases and controls. No association of vitamin D deficiency/insufficiency was found with the prevalent risk factors in cases of ischemic stroke. Conclusions: Vitamin D deficiency does not bear an association with ischemic stroke or its risk factors.
Gupta, Anu; Prabhakar, Sudesh; Modi, Manish; Bhadada, Sanjay Kumar; Lal, Vivek; Khurana, Dheeraj
... most common type of pro-vitamin A is beta-carotene. Vitamin A is also available in dietary supplements, ... retinyl acetate or retinyl palmitate (preformed vitamin A), beta-carotene (pro-vitamin A) or a combination of preformed ...
Background Vitamin D insufficiency may increase the risk for cardio metabolic disturbances in patients with primary hyperparathyroidism (PHPT). Objective To analyze the vitamin D status and indices of the metabolic syndrome in PHPT patients and the effect of vitamin D supplementation after parathyroid adenomectomy (PTX). Design and methods Double-blinded, randomized clinical trial (ClinicalTrials.gov Identifier: NCT00982722) performed at Karolinska University Hospital, Sweden, April 2008 to November 2011. One hundred and fifty consecutive patients with PHPT (119 women) were randomized after PTX, 75 to oral treatment with calcium carbonate 1000?mg daily and 75 to calcium carbonate 1000?mg and cholecalciferol 1600?IU daily over 12 months. Changes in metabolic profile and ambulatory blood pressure (BP) were analyzed. Main outcome measures were changes in metabolic factors, BP, and body composition. Results The 25-hydroxyvitamin D (25-OH-D)-level was <50?nmol/l in 76% of the patients before PTX. After PTX, glucose, insulin, and IGF1 decreased, while the 25-OH-D and the IGF-binding protein 1 increased and remained unchanged at follow-up after study medication. One year of vitamin D supplementation resulted in lower parathyroid hormone (PTH) (40 (34�52) vs 49 (38�66) ng/l) and higher 25-OH-D (76 (65�93) vs 49 (40�62) nmol/l; P<0.05). Other laboratory parameters were stable compared with after PTX. Systolic BP decreased and total bone mineral content increased in both groups. Conclusion Except for the lowering of the PTH level, no additive effect of vitamin D supplementation was seen. However, PTX proved effective in reducing insulin resistance. PMID:24026893
Norenstedt, Sophie; Pernow, Ylva; Brismar, Kerstin; Saaf, Maria; Ekip, Ayla; Granath, Fredrik; Zedenius, Jan; Nilsson, Inga-Lena
... QuickFacts Datos en espa�ol Health Professional Other Resources Vitamin E Fact Sheet for Consumers What is vitamin E and what does it do? Vitamin E ... out more about vitamin E? Disclaimer How much vitamin E do I need? The amount of vitamin ...
It is widely known that dialysis patients who are administered vitamin D preparations have a better prognosis than patients who are not. In this study, of 22 patients on maintenance dialysis who had been administered calcium (Ca) carbonate in our hospital, we investigated the dosage amount of vitamin D3 preparations after the phosphorus (P) binder was switched from Ca carbonate to the newly developed lanthanum carbonate (LC). After completely switching to LC, the dosage amount of oral vitamin D3 preparation (alfacalcidol equivalent) was significantly increased from 0.094 ?g/day to 0.375 ?g/day (P = 0.0090). No significant changes were observed in the values of serum corrected Ca, alkaline phosphatase, intact parathyroid hormone and P after switching. The administration of LC enabled complete cessation of the administration of Ca carbonate preparations, and increased the dosage amount of vitamin D3 preparations. Therefore, LC may be a useful P binder to improve patient prognosis. PMID:24953761
Hyodo, Toru; Kawakami, Junko; Mikami, Noriko; Wakai, Haruki; Ishii, Daisuke; Yoshida, Kazunari; Iwamura, Masatsugu; Hida, Miho; Kurata, Yasuhisa
Background: Weight loss (WL) is associated with a decrease in calcium absorption and may be one mechanism that induces bone loss with weight reduction. Objective: Because vitamin D supplementation has been shown to increase true fractional calcium absorption (TFCA), the goal of this study was to examine the effect of vitamin D during WL or weight maintenance (WM). Design: A randomized, placebo-controlled, double-blind 6-wk study was conducted in 82 postmenopausal women [BMI (in kg/m2; �SD): 30.2 � 3.7] with 25-hydroxyvitamin D [25(OH)D] concentrations <70 nmol/L during either WL or WM. All women were given 10 ?g vitamin D3/d and 1.2 g Ca/d and either weekly vitamin D3 (375 ?g) or a placebo equivalent to 63 ?g (2500 IU)/d and 10 ?g (400 IU)/d, respectively. We measured TFCA with the use of dual-stable isotopes, 25(OH)D, parathyroid hormone, estradiol, calcitriol, and urinary calcium at baseline and 6 wk in weight loss and vitamin D3�supplementation (WL-D; n = 19), weight maintenance and vitamin D3�supplementation (WM-D; n = 20), weight loss and placebo (n = 22), and weight maintenance and placebo (n = 21) groups. Results: WL groups lost 3.8 � 1.1% of weight with no difference between vitamin D3 supplementation and the placebo. The rise in serum 25(OH)D was greatest in the WL-D group (19.8 � 14.5 nmol/L) compared with in WM-D (9.1 � 10.3 nmol/L) and placebo groups (1.5 � 10.9 nmol/L). TFCA increased with vitamin D3 supplementation compared with placebo treatment (P < 0.01) and decreased during WL compared with WM. Serum 25(OH)D or 1,25-dihyroxyvitamin D did not correlate with TFCA. Conclusion: These data show that vitamin D supplementation increases TFCA and that WL decreases TFCA and suggest that, when calcium intake is 1.2 g/d, either 10 or 63 ?g vitamin D/d is sufficient to maintain the calcium balance. This trial was registered at clinicaltrials.gov as NCT00473031. PMID:23364004
Shapses, Sue A; Sukumar, Deeptha; Schneider, Stephen H; Schlussel, Yvette; Sherrell, Robert M; Field, M Paul; Ambia-Sobhan, Hasina
Effect of supplemental vitamin D and calcium on serum sclerostin levels
Objective Serum sclerostin has been inversely associated with serum 25OHD concentration, but the effect of supplementation with vitamin D and calcium on serum sclerostin is unknown. This study was done to determine whether supplementation altered serum sclerostin levels in healthy older adults. Design We measured serum sclerostin at baseline and after two years in 279 men and women who participated in a placebo-controlled vitamin D (700 IU per day) and calcium (500 mg per day) intervention trial in men and women age 65 years and older. Method Serum sclerostin levels were measured by MesoScale Discovery chemiluminescence assay. Results In the men, sclerostin levels increased over 2 years by 4.11 � 1.81 ng/L (13.1%) in the supplemented group and decreased by 3.16 � 1.78 ng/L (10.9%) in the placebo group (P = 0.005 for difference in change). Adjustment for season, baseline physical activity, baseline serum sclerostin and total body bone mineral content (BMC) did not substantially alter the changes. In the women, there was no significant group difference in change in serum sclerostin either before or after the above adjustments. In both sexes, supplementation significantly increased serum ionized calcium and decreased parathyroid hormone (PTH) levels. Conclusion In conclusion, men and women appear to have different serum sclerostin responses to supplementation with vitamin D and calcium. The reason for this difference remains to be determined. PMID:24488080
Dawson-Hughes, Bess; Harris, Susan S.; Ceglia, Lisa; Palermo, Nancy J.
Increased anxiety in mice lacking vitamin D receptor gene
Increased anxiety in mice lacking vitamin D receptor gene Allan V. Kalue¡,1,CA Yan-Ru Lou,1 Ilkka.0000129370.04248.92 Vitamin D is a steroid hormone with many important functions in the brain, mediated through the vitamin D nuclear receptor. Nu- merous human and animal data link vitamin D dysfunctions
Kalueff, Allan V.
Parathyroid adenoma in a patient with familial hypocalciuric hypercalcaemia.
A 57-year-old man with symptoms of fatigue, joint pains and insomnia was found to have hypercalcaemia secondary to hyperparathyroidism with a corrected calcium of 2.61?mmol/L (2.2-2.6?mmol/L) and a serum parathyroid hormone (PTH) of 86?pg/mL (10-65?pg/mL). Preoperative workup demonstrated a parathyroid adenoma in the right upper position and he proceeded to surgery. Postoperatively, however, his symptoms remained unchanged and the corrected calcium remained elevated at 2.87?mmol/L with a PTH of 59?pg/mL. He had no family history of hypercalcaemia. Further investigations revealed low 24?h urinary calcium level and a low urine calcium to creatinine ratio. Genetic testing revealed a mutation in exon 4 of the calcium sensing receptor (CaSR) confirming a diagnosis of familial hypocalciuric hyercalcaemia (FHH). The case is an example of a rare phenomenon when a parathyroid adenoma develops in patients with FHH. PMID:25320261
Forde, Hannah Elizabeth; Hill, Arnold D; Smith, Diarmuid
Vitamin D receptors in breast cancer cells
1,25-(OH)2-Vitamin D3, the active metabolite of vitamin D, is a secosteroid hormone with known differentiating activity in leukemic cells. Studies have demonstrated the presence of vitamin D receptors (VDR) in a wide range of tissues and cell types. Antiproliferative activity of 1,25-(OH)2-vitamin D3 has been documented in osteosarcoma, melanoma, colon carcinoma, and breast carcinoma cells. This study was designed to
Robert R. Buras; Lisa M. Schumaker; Fatemeh Davoodi; Richard V. Brenner; Mohsen Shabahang; Russell J. Nauta; Stephen R. T. Evans
The randomised, double blind intervention trial �Optimising Vitamin D Status in Older People� (VDOP) will test the effect of three oral dosages of vitamin D given for one year on bone mineral density (BMD) and biochemical markers of vitamin D metabolism, bone turnover and safety in older people. VDOP is funded by Arthritis Research UK, supported through Newcastle University and MRC Human Nutrition Research and sponsored by the Newcastle upon Tyne Hospitals NHS Foundation Trust.a Background Vitamin D insufficiency is common in older people and may lead to secondary hyperparathyroidism, bone loss, impairment of muscle function and increased risk of falls and fractures. Vitamin D supplementation trials have yielded conflicting results with regard to decreasing rates of bone loss, falls and fractures and the optimal plasma concentration of 25 hydroxy vitamin D (25OHD) for skeletal health remains unclear. Method/design Older (?70 years) community dwelling men and women are recruited through General Practices in Northern England and 375 participants are randomised to take 12,000 international units (IU), 24,000 IU or 48,000 IU of vitamin D3 orally each month for one year starting in the winter or early spring. Hip BMD and anthropometry are measured at baseline and 12 months. Fasting blood samples are collected at baseline and three-month intervals for the measurement of plasma 25OHD, parathyroid hormone (PTH), biochemical markers of bone turnover and biochemistry to assess the dose�response and safety of supplementation. Questionnaire data include falls, fractures, quality of life, adverse events and outcomes, compliance, dietary calcium intake and sunshine exposure. Discussion This is the first integrated vitamin D supplementation trial in older men and women using a range of doses given at monthly intervals to assess BMD, plasma 25OHD, PTH and biochemical markers of bone turnover and safety, quality of life and physical performance. We aim to investigate the vitamin D supplementation and plasma 25OHD concentration required to maintain bone health and to develop a set of biochemical markers that reflects the effect of vitamin D on bone. This will aid future studies investigating the effect of vitamin D supplementation on fracture risk. #ISRCTN 35648481 (assigned 16 August 2012), EudraCT 2011-004890-10. PMID:24041337
VITAMIN D AND LIVING IN NORTHERN LATITUDES - AN ENDEMIC RISk AREA FOR VITAMIN D DEFICIENCy
Objectives. To review the current literature on the health effects of vitamin D, especially the effects on inhabitants living in the northern latitudes. Study Design. Literature review. Methods. The scientific literature concerning health effects of vitamin D was reviewed and the current dietary recommendations for inhabitants living in northern latitudes were discussed. Results. Vitamin D is a steroid-structured hormone produced
Anne Huotari; Karl-Heinz Herzig
Local ethanol injection for the treatment of deltoid parathyroid cell hyperplasia.
Secondary hyperparathyroidism (SHPT) is a serious complication in dialysis patients and is routinely managed with medical therapy. Refractory disease is usually treated either surgically or by local ethanol injection into the parathyroid glands. Total parathyroidectomy with deltoid implant can be successful; however, recurrent, resistant disease is not uncommon. Local ethanol injection was applied to the deltoid autoimplant of a patient with recurrent, resistant SHPT, which had not been resolved with surgical treatment. Serum intact parathyroid hormone (iPTH) levels subsequently decreased from 1,400 to 219 pg/dl and remained stable for the next 6 months. To our knowledge, this procedure has not been previously described in the literature. Local injection of ethanol may represent an interesting alternative to surgery for the treatment of deltoid parathyroid cell hyperplasia in patients in which surgical treatment is not an option. PMID:23359107
Figari, M; Musso, C G; Plantalech, L; Lambertini, R; Rivera, H; Mollerach, A
... Manage a Serious Allergic Reaction Quiz: Baseball Injuries Vitamin D KidsHealth > Teens > Food & Fitness > Nutrition Basics > Vitamin ... get the recommended daily amount. Continue How Much Vitamin D Do I Need? The Institute of Medicine ( ...
Successful parathyroid tissue autograft after 3 years of cryopreservation: a case report.
After a total parathyroidectomy, well-established protocols for the cryopreservation of parathyroid tissue and for the delayed autograft of this tissue exist, especially in cases of secondary hiperparathyroidism (HPT) or familial or sporadic parathyroid hyperplasia. Although delayed autografts are effective, the published success rates vary from 10% to 83%. There are numerous factors that influence the viability, and therefore the success, of an autograft, including cryopreservation time. Certain authors believe that the tissue is only viable for 24 months, but there is no consensus on how long the parathyroid tissue can be preserved. A 63-year-old male who was diagnosed with sporadic multiple endocrine neoplasia type 1 and primary hyperparathyroidism, and was submitted to a total parathyroidectomy and an autograft in the forearm. The implant failed, and the patient developed severe hypoparathyroidism in the months following the surgery. Thirty-six months after the total parathyroidectomy, the cryopreserved autograft was successfully transplanted, and hypoparathyroidism was reversed (most recent systemic parathyroid hormone, PTH, of 36 pg/mL, and total calcium of 9.1 mg/dL; no oral calcium supplementation). The case presented here indicates that cryopreserved parathyroid tissue may remain viable after 24 months in storage, and may retain the capacity to reverse permanent postsurgical hypoparathyroidism. These data provide reasonable evidence that the time limit for cryopreservation remains undetermined and that additional research would be valuable. PMID:24863096
Leite, Ana K N; Junior, Clim�rio P do N; Arap, S�rgio S; Massoni, Ledo; Louren�o, Delmar M; Brand�o, Lenine Garcia; Montenegro, F�bio L de M
Vitamin D deficiency has been implicated in the aetiology of infectious diseases and metabolic syndrome. These diseases are prevalent in the African and Asian-Indian populations of South Africa; however, there is limited data on 25-hydroxyvitamin D (25(OH)D) concentrations in these populations. The aim of the present study was to assess the vitamin D status and its predictors in healthy adults in Johannesburg. We assessed the vitamin D status of 730 adult African and Asian-Indian subjects residing in Johannesburg. The contributions of sun exposure, season, dietary intake of Ca and vitamin D, total body fat and body fat distribution to 25(OH)D concentrations were assessed. The concentrations of 25(OH)D were measured by HPLC. The contribution of 25(OH)D? to total 25(OH)D concentrations was assessed. The mean age of the subjects was 42�6 (SD 13�1) years (range: 18-65). Concentrations of 25(OH)D < 30 nmol/l were found in 28�6 % of the Asian-Indian subjects in comparison with 5�1 % of the African subjects (P< 0�0001). Parathyroid hormone (PTH) concentrations were negatively associated with 25(OH)D concentrations, while season and sun exposure were positive predictors explaining 16 % of the variance in 25(OH)D concentrations (P< 0�0001) in the African subjects. In the Asian-Indian subjects, PTH concentrations were negatively associated with 25(OH)D concentrations, while male sex, season and Ca supplementation were positive predictors and explained 17 % of the variance in 25(OH)D concentrations (P< 0�0001). In the multivariate regression analysis, neither total body fat nor body fat distribution was predictive of 25(OH)D concentrations in either group. In conclusion, factors such as sun exposure, dietary supplement use and ethnicity are important determinants of plasma 25(OH)D concentrations. PMID:24877635
George, Jaya A; Norris, Shane A; van Deventer, Hendrick E; Pettifor, John M; Crowther, Nigel J
The purpose of the study was to identify determinants of placental vitamin D receptor (VDR) expression and placental calcium (Ca) transfer among pregnant adolescents. Placental tissue was obtained in 94 adolescents (?18 yr) at term. In 12 of these teens, stable Ca isotopes were given intravenously ((42)Ca) and orally ((44)Ca) early in labor. Placental VDR expression was assessed via Western blot and validated by RT-PCR. Maternal-to-fetal Ca transfer was calculated as the enrichment in cord blood at delivery relative to maternal serum enrichment 2 h postdosing. Isotopic study outcomes were examined in relation to fetal long bone length, placental VDR, serum 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D], and parathyroid hormone (PTH) in maternal circulation and cord blood at delivery. Placental VDR expression was inversely associated with neonatal 25(OH)D (P=0.012) and positively with neonatal 1,25(OH)2D (P=0.006). Placental VDR was a positive predictor of fetal femur length Z score (P=0.018; R(2)=0.06) and was positively correlated with maternal-to-fetal transfer of intravenous (42)Ca (P=0.004; R(2)=0.62). The fetus may regulate placental VDR expression given the significant associations with neonatal vitamin D metabolites. The association between placental VDR and fetal long bone length may indicate a role for VDR in fetal bone development, potentially by mediating transplacental Ca transfer. PMID:24558197
Young, Bridget E; Cooper, Elizabeth M; McIntyre, Allison W; Kent, Tera; Witter, Frank; Harris, Z Leah; O'Brien, Kimberly O
Vitamin D is a secosteroid of nutritional origin but can also be generated in the skin by ultraviolet light. After two hydroxylations 1,25-(OH)2 vitamin D avidly binds and activates the vitamin D receptor (VDR), a nuclear transcription factor, hereby regulating a large number of genes. The generation of VDR deficient mice has expanded the knowledge on vitamin D from a calcium-regulating hormone to a humoral factor with extensive actions. The effects of the vitamin D system on calcium and bone homeostasis are largely mediated by promoting active intestinal calcium transport via the induction of the epithelial calcium channel TRPV6. Although VDR is redundant in bone, it may regulate the differentiation and function of several bone cells. In skin, VDR expression in keratinocytes is essential in a ligand-independent manner for the maintenance of the normal hair cycle. Therefore, VDR but not vitamin D deficiency results in alopecia. Moreover, 1,25-(OH)2 vitamin D impairs the proliferation not only of keratinocytes but also of many cell types by regulating the expression of cell cycle genes, leading to a G1 cell cycle arrest. In addition, VDR inactivation in mice results in high renin hypertension, cardiac hypertrophy and thrombogenesis. Finally, a dual effect of vitamin D was observed in the immune system where it stimulates the innate immune system while tapering down excessive activation of the acquired immune system. Taken together, the vitamin D endocrine system not only regulates calcium homeostasis but affects several systems mainly by altering gene expression but also by ligand-independent actions. PMID:17161336
Bouillon, Roger; Verstuyf, Annemieke; Mathieu, Chantal; Van Cromphaut, Sophie; Masuyama, Ritsuko; Dehaes, Petra; Carmeliet, Geert
Vitamin D and bone mineral density status of healthy schoolchildren in northern India1-3
Background: Current data on the prevalence of vitamin D defi- ciency in India are scarce. Objective: We assessed the calcium-vitamin D-parathyroid hor- mone axis in apparently healthy children from 2 different socioeco- nomic backgrounds in New Delhi, India. Design: Clinical evaluation for evidence of vitamin D deficiency was carried out in 5137 apparently healthy schoolchildren, aged 10-18y,attendinglower(LSES)andupper(USES)socioeconomic statusschools.Serumcalcium,inorganicphosphorus,alkalinephos- phatase, 25-hydroxyvitamin
Raman K Marwaha; Nikhil Tandon; Devi Reddy; Rashmi Aggarwal; Rajvir Singh; Ramesh C Sawhney; Bobbin Saluja; M Ashraf Ganie; Satveer Singh
Minimally Invasive Radioguided Parathyroid (MIRP) Surgery
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Preoperative Localization and Radioguided Parathyroid Surgery
Clinical or subclinical hyperparathyroidism is one of the most com- mon endocrine disorders. Excessive secretion of parathyroid hor- mone is most frequently caused by an adenoma of 1 parathyroid gland. Unsuccessful surgery with persistent hyperparathyroidism, due to inadequate preoperative or intraoperative localization, may be observed in about 10% of patients. The conventional surgical approach is bilateral neck exploration, whereas minimally
Giuliano Mariani; Seza A. Gulec; Domenico Rubello; Giuseppe Boni; Marco Puccini; Maria Rosa Pelizzo; Gianpiero Manca; Dario Casara; Guido Sotti; Paola Erba; Duccio Volterrani; Armando E. Giuliano
VS-105: a novel vitamin D receptor modulator with cardiovascular protective effects
BACKGROUND AND PURPOSE Vitamin D receptor (VDR) modulators (VDRMs) such as calcitriol, paricalcitol and doxercalciferol are commonly used to manage hyperparathyroidism secondary to chronic kidney disease (CKD). CKD patients experience extremely high risks of cardiovascular morbidity and mortality. Clinical observations show that VDRM therapy may be associated with cardio-renal protective and survival benefits for CKD patients. However, hypercalcaemia remains a serious side effect for current VDRMs, which leads to the need for frequent dose titration and serum Ca (calcium) monitoring. Significant clinical benefits can be derived from a VDRM with cardiovascular protective effects without the hypercalcaemic liability. EXPERIMENTAL APPROACH Male Sprague�Dawley rats were 5/6 nephrectomized and 6 weeks later, after they had established uraemia, elevated parathyroid hormone levels, endothelial dysfunction and left ventricular hypertrophy, the rats were treated with VS-105, a novel VDRM. The effects of VS-105 were also tested in cultured HL-60 cells. KEY RESULTS VS-105 induced HL-60 cell differentiation with an EC50 value at 11.8 nM. Treatment (i.p., 3� a week over a period of 2 weeks) of the 5/6 nephrectomized rats by VS-105 (0.004�0.64 �g�kg?1) effectively suppressed serum parathyroid hormone without raising serum Ca or phosphate levels. Furthermore, 2 weeks of treatment with VS-105 improved endothelium-dependent aortic relaxation and attenuated left ventricular abnormalities in a dose range that did not affect serum Ca levels. Similar results were obtained when VS-105 was administered i.p. or by oral gavage. CONCLUSIONS AND IMPLICATIONS VS-105 exhibits an overall therapeutic product profile that supports expanded use in CKD to realize the cardiovascular protective effects of VDR activation. PMID:21557735
Wu-Wong, J Ruth; Kawai, Megumi; Chen, Yung-wu; Nakane, Masaki
Recently, scientists have generated a strong body of evidence providing new information about the preventive effect of vitamin D on a broad range of disorders. This evidence suggests that vitamin D is much more than a nutrient needed for bone health; it is an essential hormone required for regulation of a large number of physiological functions. Sufficient concentration of serum 25-hydroxyvitamin D is essential for optimising human health. This article reviews the present state-of-the-art knowledge about vitamin D�s status worldwide and refers to recent articles discussing some of the general background of vitamin D, including sources, benefits, deficiencies, and dietary requirements, especially in pregnancy. They offer evidence that vitamin D deficiency could be a major public health burden in many parts of the world, mostly because of sun deprivation. The article also discusses the debate about optimal concentration of circulating serum 25-hydroxyvitamin D, and explores different views on the amount of vitamin D supplementation required to achieve and maintain this concentration. PMID:22548132
Alshishtawy, Moeness Moustafa
Vitamin D and Racial Disparity in Albuminuria: NHANES 2001-2006
Background National data show unexplained racial disparity in albuminuria. We assessed whether low serum vitamin D status contributes to racial disparity in albuminuria. Methods We examined the association between race and albuminuria (spot urinary albumin/creatinine ratio (ACR) ?30) among non-Hispanic black and white nonpregnant adults who were free of renal impairment in the National Health and Nutrition Examination Survey (NHANES) from 2001�2006. We conducted analyses without and with serum 25(OH)D. We adjusted for age, sex, education level, smoking, body mass index (BMI), diabetes, diagnosis of hypertension, and use of antihypertensive medication. Results Albuminuria was present in 10.0% of non-Hispanic blacks and 6.6% in non-Hispanic whites. Being black (odds ratio (OR) 1.46; 95% confidence interval (CI) 1.23�1.73) was independently associated with albuminuria. There was a graded, inverse association between 25(OH)D level and albuminuria. Notably, the association between race and albuminuria was no longer significant (OR 1.19; 95% CI 0.97�1.47) after accounting for participants' serum 25(OH)D. Similar results were observed when participants with macroalbuminuria (ACR ?300�mg/g) or elevated parathyroid hormone (>74�pg/ml) were excluded or when a continuous measure of 25(OH)D was substituted for the categorical measure. There were no interactions between race and vitamin D status though racial disparity in albuminuria was observed among participants with the highest 25(OH)D levels. Conclusion Suboptimal vitamin D status may contribute to racial disparity in albuminuria. Randomized controlled trials are needed to determine whether supplementation with vitamin analogues reduces risk for albuminuria or reduce racial disparity in this outcome. PMID:21716328
Fiscella, Kevin A.; Winters, Paul C.; Ogedegbe, Gbenga
Health Disparities and Vitamin D
Research over the last two to three decades has slowly demonstrated that Vitamin D, a long neglected and unappreciated hormone,\\u000a is of profound importance to human health and survival. Vitamin D begins its synthesis in human skin with ultraviolet B radiation\\u000a (UVB) from the sun. Melanin is a potent UVB blocker, protecting the skin from the high intensity sunlight found
Douglass Bibuld
Health Disparities and Vitamin D
\\u000a Research over the last two to three decades has slowly demonstrated that vitamin D, a long poorly understood and unappreciated\\u000a hormone, is of profound importance to human health and survival. Vitamin D begins its synthesis in human skin with ultraviolet\\u000a B radiation (UVB) from the sun. Melanin is a potent UVB blocker, protecting the skin from the high-intensity sunlight found
Douglass Bibuld
Background Radioguided surgery using 99m-Technetium-methoxyisobutylisonitrile (99mTc-MIBI) has been recommended for the surgical treatment of mediastinal parathyroid adenomas. However, high myocardial 99mTc-MIBI uptake may limit the feasibility of radioguided surgery in aortopulmonary window parathyroid adenoma. Case presentation Two female patients aged 72 (#1) and 79�years (#2) with primary hyperparathyroidism caused by parathyroid adenomas in the aortopulmonary window were operated by transsternal radioguided surgery. After intravenous injection of 370�MBq 99mTc-MIBI at start of surgery, the maximum radioactive intensity (as counts per second) was measured over several body regions using a gamma probe before and after removal of the parathyroid adenoma. Relative radioactivity was calculated in relation to the measured ex vivo radioactivity of the adenoma, which was set to 1.0. Both patients were cured by uneventful removal of aortopulmonary window parathyroid adenomas of 4400 (#1) and 985�mg (#2). Biochemical cure was documented by intraoperative measurement of parathyroid hormone as well as follow-up examination. Ex vivo radioactivity over the parathyroid adenomas was 196 (#1) and 855 counts per second (#2). Before parathyroidectomy, relative radioactivity over the aortopulmonary window versus the heart was found at 1.3 versus 2.6 (#1) and 1.8 versus 4.8 (#2). After removal of the adenomas, radioactivity within the aortopulmonary window was only slightly reduced. Conclusion High myocardial uptake of 99mTc-MIBI limits the feasibility of radioguided surgery in aortopulmonary parathyroid adenoma. PMID:24758398
The hydrosoluble vitamins are a group of organic substances that are required by humans in small amounts to prevent disorders of metabolism. Significant progress has been made in our understanding of the biochemical, physiologic and nutritional aspects of the water-soluble vitamins. Deficiency of these particular vitamins, most commonly due to inadequate nutrition, can result in disorders of the nervous system. Many of these disorders have been successfully prevented in developed countries; however, they are still common in developing countries. Of the hydrosoluble vitamins, the nervous system depends the most on vitamins B and C (ascorbic acid) for proper functioning. The B group vitamins include thiamin (vitamin B1), riboflavin (vitamin B2), niacin or niacinamide (vitamin B3), pantothenic acid (vitamin B5), pyridoxine or pyridoxal (vitamin B6) and cobalamin (vitamin B12). Clinical findings depend upon the deficiency of the underlying vitamin; generally, deficiency symptoms are seen from a combination rather than an isolated vitamin deficiency. True hereditary metabolic disorders and serious deficiency-associated diseases are rare and in general limited to particular geographic regions and high-risk groups. Their recognition is truly important as that determines the appropriate therapeutic management. The general availability of vitamins to practically everyone and several national health programs have saved many lives and prevented complications. However, there has been some apprehension for several decades about how harmless generous dosages of these vitamins are. Overt overdosages can cause vitamin toxicity affecting various body systems including the nervous system. Systemically, vitamin toxicity is associated with nonspecific symptoms, such as nausea, vomiting, diarrhea, and skin rash which are common with any acute or chronic vitamin overdose. At a national level, recommended daily allowances for vitamins become policy statements. Nutrition policy has far reaching implications in the food industry, in agriculture, and in food provision programs. Overall, water-soluble vitamins are complex molecular structures and even today, many areas of vitamin biochemistry still need to be explored. Many readers might be of the opinion that the classic forms of nutritional deficiency diseases have faded into the background of interesting history. This has caused their diverse symptoms to be neglected by most modern physicians since vitamin enrichment of many foods automatically erases them from their consideration in differential diagnosis. Vitamin B12 and folic acid deficiencies are discussed in other chapters. PMID:24365359
Chawla, Jasvinder; Kvarnberg, David
Calcitriol, 1?, 25-dihydroxyvitamin D3 (1,25 (OH)2D3), the most active form of vitamin D, is a pleotropic hormone with a wide range of biological activities. Due to its ability to regulate calcium and phosphate metabolism, 1,25D3 plays a major role in bone health. In addition, 1,25D3 binds to the vitamin D receptor and thereby regulates the expression of a number of genes which control growth, differentiation and survival of cancer cells. In agreement, the levels of vitamin D3 appear to be an essential determinant for the development and progression of colon cancer and supplementation with vitamin D3 is effective in suppressing intestinal tumorigenesis in animal models. Vitamin D3 has been estimated to lower the incidence of colorectal cancer by 50%, which is consistent with the inverse correlation between dietary vitamin D3 intake or sunlight exposure and human colorectal cancer. Several studies confirmed that increasing vitamin D3 lowers colon cancer incidence, reduces polyp recurrence, and that sufficient levels of vitamin D3 are associated with better overall survival of colon cancer patients. Vitamin D regulates the homeostasis of intestinal epithelium by modulating the oncogenic Wnt signaling pathway and by inhibiting tumor-promoting inflammation. Both activities contribute to the ability of 1,25D3 to prevent the development and progression of colon cancer. PMID:25400874
Klampfer, Lidija
Calcitriol, 1?, 25-dihydroxyvitamin D3 (1,25 (OH)2D3), the most active form of vitamin D, is a pleotropic hormone with a wide range of biological activities. Due to its ability to regulate calcium and phosphate metabolism, 1,25D3 plays a major role in bone health. In addition, 1,25D3 binds to the vitamin D receptor and thereby regulates the expression of a number of genes which control growth, differentiation and survival of cancer cells. In agreement, the levels of vitamin D3 appear to be an essential determinant for the development and progression of colon cancer and supplementation with vitamin D3 is effective in suppressing intestinal tumorigenesis in animal models. Vitamin D3 has been estimated to lower the incidence of colorectal cancer by 50%, which is consistent with the inverse correlation between dietary vitamin D3 intake or sunlight exposure and human colorectal cancer. Several studies confirmed that increasing vitamin D3 lowers colon cancer incidence, reduces polyp recurrence, and that sufficient levels of vitamin D3 are associated with better overall survival of colon cancer patients. Vitamin D regulates the homeostasis of intestinal epithelium by modulating the oncogenic Wnt signaling pathway and by inhibiting tumor-promoting inflammation. Both activities contribute to the ability of 1,25D3 to prevent the development and progression of colon cancer.
Klampfer, Lidija
Evidence linking vitamin D to cardiovascular (CV) health has accumulated in recent years: numerous epidemiologic studies report deficiency as a significant CV risk factor, and rodent models suggest that active vitamin D can modulate critical remodeling processes, including cardiac hypertrophy and extracellular matrix remodeling. The presence of vitamin D signaling machinery within the human heart implies a direct role for this hormone in cardiac physiology and may explain associations between vitamin D status and CV outcomes. Heart failure (HF) represents a growing social and economic burden worldwide. Myocardial remodeling is central to HF development, and in the context of emerging evidence supporting mechanistic involvement of vitamin D, this review provides critical appraisal of scientific literature related to the role of vitamin D in CV disease, including data from epidemiologic and supplementation studies, as well as novel findings from animal models and in vitro work. Although associative data linking vitamin D and CV outcomes and evidence supporting a role for vitamin D in relevant pathogenic processes are both substantial, there are limited mechanistic data to indicate vitamin D supplementation as a viable therapeutic adjunct for the prevention of HF development following myocardial injury. PMID:24125108
Meredith, Anna J; McManus, Bruce M
Vitamin D: the light side of sunshine
Under normal circumstances, vitamin D is mainly obtained from skin through the action of ultraviolet B irradiation on 7-dehydrocholesterol. It is further metabolized to 25-hydroxyvitamin D (25OHD), the major circulating vitamin D compound, and then to 1,25-dihydroxyvitamin D, the hormonal form. The major function of vitamin D compounds is to enhance active absorption of ingested calcium (and phosphate). This assists
R S Mason; V B Sequeira; C Gordon-Thomson
Thalamic calcication in vitamin D receptor knockout mice
Thalamic calci¢cation in vitamin D receptor knockout mice Allan Kalue¡a , Elena Losevaa , Hannu (TAYS, Finland) and the Academy of Finland. Received 3 February 2006; accepted15 February 2006 Vitamin D is a steroid hormone with many important functions in the brain, mediated through the nuclear vitamin D
Kalueff, Allan V.
Cholecalciferol; Vitamin D3; Ergocalciferol; Vitamin D2 ... two different forms: D 2 (ergocalciferol) D 3 (cholecalciferol) ... breast-feeding teens and women One microgram of cholecalciferol (D 3 ) is the same as 40 IU ...
Vitamin C is an antioxidant. It is important for your skin, bones, and connective tissue. It promotes healing and helps the body absorb iron. Vitamin C comes from fruits and vegetables. Good sources ...
... IL: American Dietetic Association; 2007. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, ...
... of most nutrients. Should you take vitamin or mineral supplements during cancer treatment? Many researchers and clinicians ... advise their patients to avoid antioxidant vitamin and mineral supplements during treatment, but some surveys suggest this ...
... mg zinc, 400 IU vitamin E, 15 mg beta-carotene , and 2 mg copper for about 6 years ... other antioxidants (such as vitamin E, selenium, and beta-carotene) reduced the heart-protective effects of two drugs ...
... provitamin A in foods and dietary supplements is beta-carotene . Table of Contents What is vitamin A and ... retinyl acetate or retinyl palmitate (preformed vitamin A), beta-carotene (provitamin A), or a combination of preformed and ...
NASA Astrophysics Data System (ADS)
Vitamins are defined as relatively low-molecular-weight compounds which humans, and for that matter, any living organism that depends on organic matter as a source of nutrients, require small quantities for normal metabolism. With few exceptions, humans cannot synthesize most vitamins and therefore need to obtain them from food and supplements. Insufficient levels of vitamins result in deficiency diseases [e.g., scurvy and pellagra, which are due to the lack of ascorbic acid (vitamin C) and niacin, respectively].
Pegg, Ronald B.; Landen, W. O.; Eitenmiller, Ronald R.
Vitamin A plays a role in your Vision Bone growth Reproduction Cell functions Immune system Vitamin A is an antioxidant. It can come from ... vegetables. Animal sources include liver and whole milk. Vitamin A is also added to foods like cereals. ...
Vitamin D helps your body absorb calcium. Calcium is one of the main building blocks of bone. A lack of vitamin D can lead to bone diseases such as osteoporosis or rickets. Vitamin D also has a role in your nerve, ...
... labels. Can I get vitamin D from the sun? The body makes vitamin D when skin is directly exposed to the sun, and most people meet at least some of ... skin makes. However, despite the importance of the sun to vitamin D synthesis, it is prudent to ...
Ectopic parathyroid adenomas can be encountered during four gland explorations, but nearly 80% of adenomas are localized with ultrasound and sestamibi imaging. Ectopic adenomas are thought to arise from abnormal migration during development. As a cervical congenital anomaly, common carotid artery agenesis is an extremely rare anomaly characterized by separate origins of the internal and external carotid arteries directly from the aortic arch. Here we present a case of a 75 year old man with primary hyperparathyroidism who was found to have congenital agenesis of the common carotid artery associated with an ectopic parathyroid adenoma within the parapharyngeal space, which mimicked a carotid body tumor based on location and imaging. The successful identification and resection of the ectopic parathyroid adenoma presented here demonstrate the importance of preoperative imaging studies to allow appropriate operative planning as well as the utility of intraoperative parathyroid hormone assay in predicting cure during surgery. PMID:23993711
Malm, Ian-James; Olcott, Clara M; Chan, Jason Y K; Loyo, Myriam; Kim, Young J
Fine-Needle Aspiration Cytology of Parathyroid Carcinoma Mimic H?rthle Cell Thyroid Neoplasm
Background. Fine-needle aspiration (FNA) can cause misdiagnosis of cytomorphological findings between parathyroid and thyroid lesions. Case Presentation. A 31-year-old man presented with a palpable neck mass on the right thyroid lobe. FNA cytology was reported as intrathyroidal lymphoid hyperplasia. After 5 years, repeated FNA was done on the enlarged nodule with result of H�rthle cell lesion. Prior to right lobectomy, laboratories revealed elevated serum calcium and parathyroid hormone (PTH). Careful history taking revealed chronic knee pain and ossifying fibroma at the maxilla. Ultrasonography showed a 2.8?cm mass inferior to right thyroid lobe. Pathology from en bloc resection was parathyroid carcinoma and immunohistochemical study revealed positivity for PTH. Genetic analysis found somatic mutation of CDC73 gene in exon1 (c.70delG) which caused premature stop codon in amino acid 26 (p.Glu24Lysfs*2). The final diagnosis was hyperparathyroidism-jaw tumor syndrome. Conclusions. FNA cytology of parathyroid can mimic thyroid lesion. It is important to consider and correlate the entire information from clinical history, laboratory, imaging, and FNA. PMID:25177504
Sornmayura, Pattana; Chanplakorn, Niramol; Trachoo, Objoon; Sae-Chew, Pattarana; Aroonroch, Rangsima
Intact parathyroid hormone (PTHi) has a relatively short half-life and levels fall significantly within 15 min of the successful excision of all the abnormal parathyroid glands during surgery for hyperparathyroidism. Monitoring this fall has been suggested as useful in decreasing the failure rate of neck explorations in parathyroid surgery. We have performed a comparative study of the use, during surgery for primary hyperparathyroidism, of routine frozen section with the recently available rapid assay for PTHi. The assay demonstrated a significant fall (P = 0.013) in the level of PTHi from a pre-excision mean of 26.66 pmol/l to 5.94 pmol/l 15 min after surgical excision. In all cases the level of PTHi fell to less than 30% of pre-excision levels by 30 min. However, while frozen section results were available in a mean time of 22 min after excision, the PTHi levels took a mean of 105 min. We conclude that during straightforward parathyroid surgery for primary hyperparathyroidism, the current assay does not offer any advantages over the already routine use of frozen section. PMID:8422140
Madira, W.; Robertson, G. S.; London, N. J.; Iqbal, S. J.; Bell, P. R.; Veitch, P. S.
The use of cinacalcet in pregnancy to treat a complex case of parathyroid carcinoma
Summary We present the case of a patient with metastatic parathyroid carcinoma whose hypercalcaemia was medically managed through two pregnancies. The diagnosis was made when the patient presented with chronic knee pain and radiological findings consistent with a brown tumour, at the age of 30. Her corrected calcium and parathyroid hormone (PTH) levels were significantly elevated. Following localisation studies, a right parathyroidectomy was performed with histology revealing parathyroid carcinoma, adherent to thyroid tissue. Aged 33, following biochemical recurrence of disease, the patient underwent a second operation. A subsequent CT and FDG�PET revealed bibasal pulmonary metastases. Aged 35, the patient was referred to our unit for treatment of persistent hypercalcaemia. The focus of treatment at this time was debulking metastatic disease using radiofrequency ablation. Despite advice to the contrary, the patient conceived twice while taking cinacalcet. Even though there are limited available data regarding the use of cinacalcet in pregnancy, both pregnancies continued to term with the delivery of healthy infants, using intensive medical management for persistent hypercalcaemia. Learning points Parathyroid carcinoma is a rare cause of primary hyperparathyroidism.Hypercalcaemia during pregnancy can result in significant complications for both the mother and the foetus.The use of high-dose cinacalcet in pregnancy has been shown, in this case, to aid in the management of resistant hypercalcaemia without teratogenicity. PMID:25298882
Bailey, M; Chahal, H; Raja, O; Bhat, R; Gayle, C; Grossman, A B; Druce, M R
Imaging techniques in parathyroid surgery for primary hyperparathyroidism
As more patients present with the incidental diagnosis of primary hyperparathyroidism due to biochemical screening, treatment guidelines have been developed for the treatment of hyperparathyroidism. Management of primary hyperparathyroidism has evolved in recent years with considerable interest in minimally invasive approaches. Successful localization of the diseased gland(s) by nuclear imaging and anatomical studies along with rapid intraoperative parathyroid hormone assay has allowed for focused and minimally invasive surgical approaches. Patients in whom the localization studies have identified single gland adenoma or unilateral disease are candidates for such focused approaches instead of the traditional approach of bilateral exploration. These imaging techniques have also been critical in the successful management of patients with persistent or recurrent disease. PMID:22154018
Mohebati, A.; Shaha, A.R.
Correlates of HIV-1 shedding in cervical and vaginal secretions were investigated in a cross-sectional study of 318 women previously diagnosed with HIV who presented to a sexually transmitted disease clinic in Mombasa, Kenya, during 1994-96. HIV-infected cells were detected in 51% of endocervical and 14% of vaginal swab specimens. Both cervical and vaginal shedding of HIV-1 infected cells were highly associated with CD4 lymphocyte depletion. After adjustment for CD4 count, cervical proviral shedding was significantly associated with use of depo medroxyprogesterone acetate (odds ratio [OR], 2.9; 95% confidence interval [CI], 1.5-5.7) and of low- and high-dose oral contraceptives (OR, 3.8; 95% CI, 1.4-9.9 and OR, 12.3; 95% CI, 1.5-101, respectively). After adjustment for CD4 count, severe vitamin A deficiency, moderate deficiency, and low-normal vitamin A status were associated with 12.9, 8.0, and 4.9-fold increased odds of vaginal shedding, respectively. Finally, gonococcal cervicitis (OR, 3.1; 95% CI, 1.1-9.8) and vaginal candidiasis (OR, 2.6; 95% CI, 1.2-5.4), but not Chlamydia trachomatis and Trichomonas vaginalis, were correlated with significant increases in HIV-1 DNA detection. These risk factors, easily modifiable by simple interventions, may be important determinants of sexual or vertical HIV transmission. PMID:9314871
Mostad, S B; Overbaugh, J; DeVange, D M; Welch, M J; Chohan, B; Mandaliya, K; Nyange, P; Martin, H L; Ndinya-Achola, J; Bwayo, J J; Kreiss, J K
Vitamin D has received a lot of attention recently as a result of a meteoric rise in the number of publications showing that vitamin D plays a crucial role in a plethora of physiological functions and associating vitamin D deficiency with many acute and chronic illnesses including disorders of calcium metabolism, autoimmune diseases, some cancers, type 2 diabetes mellitus, infectious diseases and cardiovascular disease. The recent data on vitamin D from experimental, ecological, case-control, retrospective and prospective observational studies, as well as smaller intervention studies, are significant and confirm the sunshine vitamin�s essential role in a variety of physiological and preventative functions. The results of these studies justify the recommendation to improve the general vitamin D status in children and adults by means of a healthy approach to sunlight exposure, consumption of foods containing vitamin D and supplementation with vitamin D preparations. In general, closer attention should therefore be paid to vitamin D deficiency in medical and pharmaceutical practice than has been the case hitherto. PMID:24516687
Grober, Uwe; Spitz, Jorg; Reichrath, Jorg; Kisters, Klaus; Holick, Michael F
Low serum 25-OHD in female Arab subjects, which may predispose their infants to hypocalcaemia, has been suggested to be due to inadequate sunshine exposure, but may include other sociobiological factors. The effects of duration of sunshine exposure--weighted against the magnitude of clothing (UV exposure) and other sociobiological variables such as age, education and living accommodation--on serum 25-OHD and mineral status of 33 UAE national women of childbearing age were compared with those of 25 non-Gulf Arabs and seventeen Europeans. Serum concentrations of calcium, phosphorus, alkaline phosphatase and intact parathyroid hormone among the groups were not significantly different. The serum concentration of 25-OHD in UAE nationals was 8.6 ng/ml (4.5-17.4), mean +/- 1 SD, and in non-Gulf Arabs 12.6 ng/ml (6.0-26.4); both these values were significantly lower (p = < 0.0001) than the 64.3 ng/ml (49-84.3) found in Europeans. Compared with Europeans, the UAE and non-Gulf Arabs in this study were younger, had fewer years of education and had significantly lower clothing and UV scores (p < 0.0001). Furthermore, there was a positive correlation (r = 0.59425) between serum 25-OHD and UV score, but not with length of exposure. After adjusting for other confounding variables, nationality, clothing and UV scores remained major determinants of serum 25-OHD (p < 0.0001). Therefore, limited skin exposure to sunlight appears to be an important determinant of vitamin D status in our subjects. Strategies to increase vitamin D stores should include vitamin D supplementation or advice on effective sunlight exposure. PMID:9818552
Dawodu, A; Absood, G; Patel, M; Agarwal, M; Ezimokhai, M; Abdulrazzaq, Y; Khalayli, G
A growing body of evidence supports an association between vitamin D and cardiovascular disease. However, the mechanisms underlying this association are unknown. From 2000 to 2002, we identified 946 participants with stable cardiovascular disease in San Francisco, California, and followed them prospectively for cardiovascular events (heart failure, myocardial infarction, stroke, or cardiovascular death). We then examined the extent to which the association was attenuated by adjustment for poor health behaviors, comorbid health conditions, and potential biological mediators. During a median follow-up period of 8.0 years (through August 24, 2012), 323 subjects (34.1%) experienced a cardiovascular event. Following adjustment for sociodemographic factors, season of blood measurement, health behaviors, and comorbid conditions, 25-hydroxyvitamin D levels under 20 ng/mL remained independently associated with cardiovascular events (hazard ratio = 1.30, 95% confidence interval: 1.01, 1.67). However, after further adjustment for potential biological mediators, the independent association was no longer present (hazard ratio = 1.11, 95% confidence interval: 0.85, 1.44). Parathyroid hormone, a potentially modifiable biological factor downstream from 25-hydroxyvitamin D, was responsible for the majority of this attenuation. These findings highlight the need for randomized controlled trials to determine whether vitamin D supplementation in persons with deficiency could be beneficial for the primary or secondary prevention of cardiovascular events. PMID:24699783
Welles, Christine C; Whooley, Mary A; Karumanchi, S Ananth; Hod, Tammy; Thadhani, Ravi; Berg, Anders H; Ix, Joachim H; Mukamal, Kenneth J
Noninvasive Imaging of Osteoclasts in Parathyroid HormoneInduced Osteolysis
metastases cause significant morbidity, including pain, pathologic frac- ture, spinal cord compression, and hypercalcemia (1,2). In addition, microscopic bone tumor metastases appear to be an independent predictor of poor outcome in breast cancer even among lymph nodenegative patients with primary tumors smaller than
Larson-Prior, Linda
Primary hyperparathyroidism occurs as a result of isolated parathyroid adenoma in 80% to 85% of all cases. A 99mtechnetium (99mTc) sestamibi scan or neck ultrasonography is used to localize the neoplasm prior to surgical intervention. A 53-year-old female was referred for the exclusion of metabolic bone disease. She presented with low back pain that had persisted for the past 6 months and elevated serum alkaline phosphatase (1,253 IU/L). Four years previously, she had been diagnosed at a local hospital with a 2.3-cm thyroid nodule, which was determined to be pathologically benign. Radiofrequency ablation was performed at the same hospital because the nodule was still growing during the follow-up period 2 years before the visit to our hospital, and the procedure was unsuccessful in reducing the size of the nodule. The results of the laboratory tests in our hospital were as follows: serum calcium, 14.6 mg/dL; phosphorus, 3.5 mg/dL; and intact parathyroid hormone (iPTH), 1,911 pg/mL. Neck ultrasonography and 99mTc sestamibi scan detected a 5-cm parathyroid neoplasm in the left lower lobe of the patient's thyroid; left parathyroidectomy was performed. This case indicated that thyroid ultrasonographers and pathologists need to be experienced enough to differentiate a parathyroid neoplasm from a thyroid nodule; 99mTc sestamibi scan, serum calcium, and iPTH levels can help to establish the diagnosis of parathyroid neoplasm. PMID:24396684
Kim, Ho-Su; Choi, Bong Hoi; Park, Jung Rang; Hahm, Jong Ryeal; Jung, Jung Hwa; Kim, Soo Kyoung; Kim, Sungsu; Kim, Kyong-Young; Chung, Soon Il
Vitamin C is a water soluble vitamin which is mainly fresh fruits and vegetables foodborne. Vitamin C deficiency is most often due to a lack of daily amount. Scurvy is characterized by the occurrence of fatigue, myalgia, arthralgia, purpura, bleeding disorders, and later by dental manifestations. Biological signs are nonspecific: anemia, hypocholesterolemia, hypoalbuminemia. Clinical suspicion is confirmed by the decrease in ascorbic acid level (< 2 mg/L). It must be interpreted in light of the acute phase reactants. The treatment is the administration of 1 g of vitamin C per day for 15 days. Vitamin C depletion (ascorbic acid: 2 to 5 mg/L) could induce long-term complications. The recommended dietary allowance of vitamin C protect from these risks. PMID:24298827
Fain, Olivier
Vitamin D and cardiovascular disease.
It has long been known from case series that vitamin D excess can lead to atherosclerosis and vascular calcification in humans. In the 1980s, ecological studies provided data that deficient human vitamin D status may also increase the risk of developing cardiovascular disease (CVD). The assumption of a biphasic vitamin D effect on CVD is supported by experimental studies: Numerous studies have demonstrated positive effects of the vitamin D hormone (1,25-dihydroxyviramin D) on the cardiovascular system. However, the effects and mechanisms that lead to vascular calcification by vitamin D excess could also be confirmed. Large prospective observational studies support the hypothesis of a U-shaped association between vitamin D and CVD. These studies indicate that deficient circulating 25-hydroxyvitamin D levels (<30 nmol/l) are independently-associated with increased CVD morbidity and mortality. They also suggest that those circulating 25-hydroxyvitamin D levels, which have long been considered to be safe (100-150 nmol/l), are associated with an increased CVD risk. Meanwhile, numerous randomized controlled trials have investigated the effects of vitamin D supplements or ultraviolet B radiation on biochemical cardiovascular risk markers, cardiovascular physiology, and cardiovascular outcomes. Overall, results are mixed with the majority of studies reporting neither beneficial nor adverse vitamin D effects. Several limitations in the study design, which may have prevented beneficial vitamin D effects, are discussed. In conclusion, it must be stated that the role of vitamin D in the prevention and management of CVD as well as the dose-response relationship of potentially harmful effects still remain to be established. PMID:25202039
Zittermann, Armin
OBJECTIVE: There is considerable debate about whether double parathyroid adenomas are a discrete entity or represent hyperplasia with parathyroid glands of varying sizes. This distinction is important because it impacts on the extent of parathyroid resection and the success of the parathyroid operation. SUMMARY BACKGROUND DATA: Double parathyroid adenomas have been reported to occur in 1.7% to 9% of patients with primary hyperparathyroidism (HPT). It is important for surgeons to differentiate between double adenoma and hyperplasia with glands of varying sizes using gross examination during the initial procedure because microscopic findings of a small biopsy specimen at frozen-section examination may not be diagnostic. METHODS: From 1982 to 1992, 416 unselected patients (309 women and 107 men) with primary HPT without familial HPT or multiple endocrine neoplasia (MEN) were treated by one surgeon at the University of California at San Francisco. Double adenoma occurred in 49 patients, solitary adenoma in 309 patients, and hyperplasia in 58 patients. The authors analyzed the clinical manifestations, the preoperative and postoperative serum levels of calcium, phosphate, and parathyroid hormone (PTH), and the success rate and outcome after parathyroidectomy and compared their results in 49 patients with double adenomas to the results for patients with solitary adenomas or hyperplasia. RESULTS: Ten of the patients with double adenomas (20.4%) were referred for persistent HPT after removal of one abnormal parathyroid gland. The ages of the patients with double adenoma, single adenoma, and hyperplasia were 61 +/- 14, 56 +/- 15, and 58 +/- 7 years, respectively. Fatigue, muscle weakness, and bone pain were common in patients with double adenomas, whereas nephrolithiasis occurred more frequently in patients with solitary adenoma (p = 0.0001). Serum calcium and PTH levels (per cent of upper limit of normal) fell from 11.5 +/- 1.2 mg/dL and 487% to 9.5 +/- 0.8 mg/dL and 61% for patients with double adenomas; from 11.9 +/- 0.9 mg/dL and 378% to 9.3 +/- 1.4 mg/dL and 101% for patients with single adenoma; and from 10.9 +/- 0.5 mg/dL and 418% to 9.1 +/- 0.7 mg/dL and 94% for patients with hyperplasia, respectively. There was no recurrence in the patients with double adenomas with a mean follow-up time of 5.8 years. CONCLUSIONS: Double adenomas are a discrete entity and occur more often in older patients. Patients with double adenomas can be successfully treated by removal of the two abnormal glands. Images Figure 1. PMID:8103983
Tezelman, S; Shen, W; Shaver, J K; Siperstein, A E; Duh, Q Y; Klein, H; Clark, O H
... other B vitamins, such as niacin, riboflavin, vitamin B6, and magnesium. A prescription form of vitamin B12 ... Board. Dietary Reference Intakes: Thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline . ...
... process your body uses to get or make energy from the food you eat. They also help form red blood cells. You can get B vitamins from proteins such as fish, poultry, meat, eggs, and dairy products. Leafy green vegetables, beans, and peas also have B vitamins. ...
Vitamin D Effects on Pregnancy and the Placenta
Vitamin D is a pleiotropic secosteroid hormone important for health and disease prevention. The actions of vitamin D are mediated by the vitamin D receptor that binds the active form of vitamin D [1,25(OH)2D] to induce both transcriptional and non-genomic responses. Vitamin D has well known classical functions in calcium uptake and bone metabolism, but more recent work highlights the importance of the nonclassical actions of vitamin D in a variety of cell types. These actions include modulation of the innate and adaptive immune systems and regulation of cell proliferation. Adequate vitamin D intake is essential for maternal and fetal health during pregnancy, and epidemiological data indicate that many pregnant women have sub-optimal