osteoarthritis ( oa ) is the most common form of arthritis and a growing burden on the public healthcare . evidence has emerged that patients with oa have increased cardiovascular ( cv ) morbidity and mortality [ 1 , 2 ] ; however , very little is known about the exact mechanism underlying this association . several potential mechanisms such as obesity , chronic systemic inflammation , balance of adipokine levels , limited physical activity , and use of nonsteroid anti - inflammatory drugs might be involved in the elevated risk of cv disease ( cvd ) in oa [ 3 , 4 ] . the adipokines are white - adipose - tissue derived cell signaling proteins that participate in multiple homeostasis maintaining functions . evidence is accumulating on multiple adipokines among which leptin and adiponectin have been most thoroughly investigated . leptin has been associated with cv events , mortality , and diabetes [ 6 , 7 ] . adiponectin has been shown to have anti - inflammatory , antiatherogenic , and cardiomyocyte protective properties in experimental settings . however , in human population this role seems to be far more complex as higher concentrations have been linked to increased cv morbidity and mortality . studies have shown that oa chondrocytes produce more leptin inducing thereby the production of cartilage degradation enzymes . adiponectin seems to possess a protective role in oa through downregulating inflammatory mediators and upregulating protease inhibitors . arterial stiffness has been shown to be an independent determinant of cv morbidity and mortality and has been proposed as a surrogate endpoint for cvd . arterial stiffness can be measured noninvasively and cf - pwv as a marker of aortic stiffness is considered the gold standard method . it is noteworthy that systemic inflammation and adipokines that have been associated with oa are also involved in the pathogenesis of arterial stiffness . aortic elastic properties have been found to be elevated in radiographically established osteoarthritis . at the same time , no association has been found between knee bone marrow lesions and cf - pwv . a better understanding of the associations between oa , adipokines , and cvd might help extend future management strategies of oa beyond the current focus on treating only chronic symptoms prior to total joint replacement . the aim of this study was to find out whether oa is associated with arterial stiffness and adipokine levels . this cross - sectional study included 70 patients with primary end - stage hip and knee oa , who presented for total joint arthroplasty , and 70 age and gender matched controls . the oa patients were elected from the traumatology and orthopaedics clinic of tartu university hospital prior to hip and knee replacement surgery . all patients were diagnosed according to the american college of rheumatology criteria for knee and hip oa [ 15 , 16 ] . patients with any acute or chronic inflammatory disease , diabetes , coronary artery disease , cardiac arrhythmias or known valve pathology , peripheral atherosclerotic disease , malignancies , or renal insufficiency ( egfr < 60  ml / min/1.73  m ) were excluded . age and gender matched apparently healthy controls were recruited through local family physicians in the same geographical region . the exclusion criteria for the control group were the following : any acute or chronic inflammatory disease , any persistent knee or hip joint pain , a visit to family practitioner because of hip or knee joint complaints , diabetes , hypertension , coronary artery disease , cardiac arrhythmia , cerebrovascular or peripheral artery disease , malignancies , renal insufficiency , and regular use of any medication . the study was conducted in accordance with the helsinki declaration and was approved by the ethics committee of the university of tartu . written informed consent was obtained from all participants . blood samples were collected between 07:00 and 11:00 after an overnight fast and abstinence from tobacco and alcohol . the height and weight and waist and hip circumference of the patients were recorded and joint - specific evaluation was performed . the harris hip score ( hhs )   was used for hip joint evaluation and the hospital for special surgery ( hss ) knee score   was used for knee joint evaluation . both of these test results range from 0 to 100 , where 100 is the best possible outcome . after 1015 minutes of rest in a temperature controlled quiet room in a supine position , the participants ' blood pressure and pulse wave velocity were recorded and pulse wave analysis was made . all pulse wave parameters were measured at least in duplicate and the average was calculated . pulse wave analysis and velocity left radial artery waveforms were recorded with a high fidelity micromanometer ( spt-301bh , millar instruments , tx , usa ) . corresponding ascending aortic waveforms were then generated using a transfer function to calculate central hemodynamics and augmentation index ( aix ) . the cf - pwv and carotid - radial pulse wave velocity ( cr - pwv ) were measured by sequentially recording ecg - gated carotid and femoral or radial artery waveforms using a sphygmocor device ( sphygmocor , atcor medical , sydney , australia ) . the pulse waveform was recorded from the right radial artery with a cardiovascular profiling instrument ( hdi / pulsewave cr-2000 , hypertension diagnostics inc . , eagan , usa ) and large ( c1 ) and small ( c2 ) artery elasticity indices were recorded . venous blood samples were centrifuged at room temperature and the serum was stored at 70c until analysis . serum adiponectin levels were measured using an enzyme - linked immunosorbent assay ( elisa ) ( human total adiponectin / acrp30 immunoassay , r&d systems europe , abingdon , uk ) . human total mmp-3 immunoassay kits available from r&d systems a bio - techne brand ( catalogue number dmp 300 ) were used for quantitative determination of human active and promatrix metalloproteinase 3 ( total pro - mmp-3 ) concentrations . the level of serum leptin was determined using the evidence investigator ( metabolic syndrome array-1 , randox laboratories , crumlin , uk ) . the serum levels of triglycerides , total cholesterol , ldl - cholesterol , hdl - cholesterol , white blood cell ( wbc ) count , high - sensitivity c - reactive protein ( hs - crp ) , serum creatinine , and egfr were measured using standard laboratory methods in the local clinical laboratory with automated analyzers . osteoarthritis was assessed according to the kellgren - lawrence grading system , where 0 represents no changes ; 1 represents doubtful joint space narrowing ; 2 represents definite osteophytes and doubtful joint space narrowing ; 3 represents definite osteophytes , joint space narrowing , sclerosis , and possible deformity ; and 4 represents marked joint space narrowing , large osteophytes , severe sclerosis , and definite bone deformity . the radiographs were evaluated independently by two raters blinded to the clinical data and a consensus score was produced . intraclass correlation coefficient ( icc ) was used to assess the consistency among the raters . the icc was found to be 0.76 , 95% ci ( 0.610.85 ) , which is considered good . , chicago il , usa ) for windows . the mann - whitney u test was used for comparing means between two groups . since there was a significant difference of bmi and blood pressure between the study groups , the levels of pwv were adjusted for bmi and mean arterial pressure and the levels of adipokines were adjusted for bmi before analysis . spearman 's rho was used for determining correlation between variables . a chi - square test or fischer 's exact test a total of 140 subjects ( women 49% , aged 4979 , and mean 61 years ) participated in the study . the level of bmi and the w / h - ratio were significantly higher , and hhs and hss knee scores were lower for the oa group . peripheral and central blood pressure were higher in the oa group . since there was a discrepancy in bmi and blood pressure ( a determinant of pwv ) between the study groups , the corresponding hemodynamic and biochemical variables were adjusted for mean arterial pressure and bmi . the cf - pwv was higher and c2 was lower for the oa group compared to the controls . the levels of leptin , wbc , hs - crp , and urea were higher and adiponectin and hdl - cholesterol were lower for the patient group ( table 3 ) . however , after correcting for bmi , the difference in hs - crp and platelet count was no longer significant and of borderline significance for adiponectin . a significant positive association was found between oa radiographic kellgren - lawrence grade and cf - pwv ( r = 0.272 , p = 0.023 ) ( figure 1(a ) ) . the association was further analyzed separately in the hip and knee subgroups ( r = 0.396 , p = 0.011 and r = 0.351 , p = 0.062 , resp . ) . multiple linear regression analysis using a stepwise selection procedure was performed to study the association between oa grade and cf - pwv . in the hip oa group cf - pwv was set as the dependent variable , and oa grade , age , mean arterial pressure ( map ) , and hs - crp remained significant independent predictors ( table 4(a ) ) . in the knee oa group , after adjusting for w / h - ratio and age , oa grade was not an independent predictor of cf - pwv ( table 4(b ) ) . in addition , kellgren - lawrence grade correlated positively with mmp-3 ( r = 0.235 , p = 0.05 ) ( figure 1(b ) ) and negatively with leptin ( r = 0.246 , p = 0.040 ) . however , furthermore , we found that adiponectin was correlated with c1 and aix@75 ( r = 0.249 , p = 0.003 and r = 0.293 , p < 0.001 , resp . ) ( figure 2 ) . in the model where adiponectin was set as the dependent variable , neither c1 nor aix were independent predictors when potential confounders were included ( data not shown ) . our study describes associations between adipokines , mmp-3 , and parameters of arterial stiffness in older adults with hip and knee oa and compares them with the corresponding indicators for asymptomatic controls . to our knowledge , this study is the first to demonstrate independent correlation between radiographic oa grade and cf - pwv . these findings support the notion that arterial stiffening might be linked to the pathogenesis of oa . in addition , we demonstrate that adipokines are associated with oa and with arterial stiffness and might thus play a role in linking these two pathologies . recently , a study of 80 end - stage knee oa patients found decreased elastic properties of aorta compared to non - oa controls . in addition , the authors found that radiographic severity of oa was associated with aortic stiffness . however , another study of knee oa patients found no relationship between presence or size of bone marrow lesions ( a surrogate for oa ) and cf - pwv . hand oa has been linked to arterial stiffness , but the relationship was largely attributable to the confounding effect of age . so far the relevant evidence has been controversial and to the best of our knowledge data concerning hip oa and arterial stiffness is lacking . in the present study of knee and hip oa we demonstrated independent association between oa severity and cf - pwv ( figure 1 , table 4 ) . we studied patients with hip oa , which is considered a different entity of oa , and found its independent association with cf - pwv . the reason for failing to reveal significant association between knee oa severity and cf - pwv might be attributed to too small sample size . yet we established relationship between hip oa and arterial stiffness , which might contribute to the higher cvd risk among oa population . the adipokines are a growing family of white - adipose - tissue derived factors that have multiple functions through different pathways and are involved in inflammation and modulation of immunological response but also in glucose and lipid metabolism . leptin upregulates mmps and induces cartilage loss [ 2123 ] ; however , its anabolic effects have also been described . although leptin has been associated with oa severity , the pathophysiological pathways are not fully understood . in addition to bone and cartilage , leptin influences also the cardiovascular system . it is an independent predictor of myocardial infarction and stroke and has been associated with increased arterial stiffness   through promoting inflammation and mmp upregulation . in accord with previous studies , we found an elevated expression of leptin in oa patients and , in addition , an inverse association with oa radiographic grade , which might indicate the anabolic effect of leptin . these findings point to the possible key role of leptin in the pathogenesis of oa and suggest leptin as a link between oa and vascular damage . adiponectin is prevalently synthesised in adipose tissue and circulates in the blood in large quantities . adiponectin has anti - inflammatory properties and hypoadiponectinemia has a detrimental effect on aortic stiffness . in the present study , adiponectin correlated inversely with large artery elasticity index and positively with aix@75 . to the best of our knowledge , findings similar to ours were reported in essential hypertension , but inverse association was recently found in juvenile idiopathic arthritis patients . our results suggest that adiponectin as well as leptin might link oa with increased arterial stiffness . these findings describe the pleiotropic role of adipokines in oa and need further research to determine their potential as therapeutic targets . the mmp-3 is a catabolic enzyme that not only has the ability to degrade the extracellular matrix but plays a central role in activating other members of the mmp family . we found higher level of mmp-3 in oa patients compared to controls and positive correlation between radiographic grade and serum level of mmp-3 in oa subjects . the activation and secretion of mmp-3 are driven by inflammatory cytokines , which in turn enhances the production of inflammatory mediators like interleukin-1 . this is in line with our results , according to which oa group also showed higher values of wbc , which indicates a systemic inflammatory state in these patients . furthermore , mmp-3 is likely to influence arterial stiffness and has been found to be elevated in atherosclerotic aorta [ 33 , 34 ] . in conclusion , mmp-3 might be another marker that is associated with oa and vascular pathology . first , because of the cross - sectional study design , causal associations could not be established . second , since x - rays for the control group were not available , some asymptomatic oa cases might be included in the controls . third , data concerning physical activity was not collected but has been shown to influence arterial stiffness and , therefore , is a confounding factor that was not accounted for in the present study . in conclusion , these relationships provide a potential link between biochemical and functional alterations and oa as well as elevated cv risk in end - stage oa .
objective . osteoarthritis ( oa ) is associated with increased cardiovascular comorbidity and mortality . 
 evidence is lacking about whether arterial stiffness is involved in oa . 
 the objective of our study was to find out associations between oa , arterial stiffness , and adipokines . 
 design . 
 seventy end - stage knee and hip oa patients ( age 62  7 years ) and 70 asymptomatic controls ( age 60  7 years ) were investigated using the applanation tonometry to determine their parameters of arterial stiffness . 
 serum adiponectin , leptin , and matrix metalloproteinase 3 ( mmp-3 ) levels were determined using the elisa method . 
 correlation between variables was determined using spearman 's rho . 
 multiple regression analysis with a stepwise selection procedure was employed . 
 results . 
 radiographic oa grade was positively associated with increased carotid - femoral pulse wave velocity ( cf - pwv ) ( r = 0.272 , p = 0.023 ) . 
 we found that oa grade was also associated with leptin and mmp-3 levels ( rho = 0.246 , p = 0.040 and rho = 0.235 , p = 0.050 , resp . ) . 
 in addition , serum adiponectin level was positively associated with augmentation index and inversely with large artery elasticity index ( rho = 0.293 , p = 0.006 and rho = 0.249 , p = 0.003 , resp . ) . 
 conclusions . 
 our results suggest that oa severity is independently associated with increased arterial stiffness and is correlated with expression of adipokines . 
 thus , increased arterial stiffness and adipokines might play an important role in elevated cardiovascular risk in end - stage oa .