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Spider Plant Problems!!! :(
Growing up my mom had TONS of plants.. after she passed away March 2010, I got her last two.. one is some type of vine plant that she got the day I was born from my Great Grandma (back in 1985) that is doing okay now finally.. the other is a Spider plant.. and he's just not doing well at all.. Id like to try to save him but honestly I dont know how.. When I first took him he was doing okay, had a couple babies hanging off of him that I clipped and put in cups of water, theyre doing good, but hes sad, not standing up the leaves are softening and drooping and even breaking at the base.. the ends are turning brown.. and now I just noticed mold on the base of the plant. I know not to over water him and I dont put him by the windows or anything. Id like to save him if I can but I dont know if its possible!? What should I do!? I really dont want to loose one of the only plants I got left of my Moms.
Hi. Welcome to GardenWeb.
I agree, more light. You wouldn't want to suddenly put your plant outside, but it can handle a lot of direct sun. An east window, as suggested above, would be great.
It sounds like the soil could be staying too wet - brown tips would be an indicator of that, and mold is absolutely a sign of too much moisture. A plant that truly needs a drink will be much lighter when you lift the pot. A plant that is not getting enough light will not use the moisture in the pot fast enough.
If you would be interested in posting some pics, more specific advice would be possible.
The good news is, as long as the little plantlets remain viable, you still have your mom's plant, even if the larger plant doesn't make it, so don't despair.
Here are some spider plant tips, and a link below to some basics that should be really helpful for beginners. I really hope you find it helpful.
While necrotic leaf tips or margins can occur in this plant from over/under-watering, in fact, it's much more common for the actual cause to be a high level of soluble salts in soils. It's also commonly reported that this plant is particularly intolerant or fluoride, but it's still more common for the cause of leaf burn to be a high level of solubles, to which fluoride can be a contributor, than it is to be fluoride itself. WHEN there is a high level of salts in the soil, low humidity can be a contributor, but low humidity alone rarely presents an issue, it must be in combination with a high level of soluble salts in the soil and either over/under-watering.
Of course, you cannot correct the already burned tips (they won't 'heal'), but you can take steps to keep it from happening:
A) Most important is to use a soil that drains very freely. This allows you to water copiously, flushing the accumulating salts from the soil each time you water.
B) Fertilize frequently when the plant is growing well, but at low doses - perhaps 1/4 the recommended strength. This, in combination with the favorable watering habit described above, will keep soluble salts levels low, and keep levels from rising due to the accumulative effect we always see when we are forced to water in sips when plants are in water-retentive soils.
C) When watering, using rainwater, snow melt, water from your dehumidifiers, or distilled water also eliminates the soluble salts in your tap water and will go a long way toward eliminating or minimizing leaf burn.
D) If you make your own soils and use perlite, be sure the perlite is rinsed thoroughly, which removes most of the fluorides associated with it's use.
E) Allowing water to rest overnight doesn't/won't do anything in the way of helping reduce the amount of fluoride (the compounds are not volatile), and it only helps with chlorine in a very few cases, depending on what method of chlorination was used to treat your tap water; but nearly all municipalities are currently using chlorination compounds that are entirely nonvolatile, which means they won't dissipate into the air.
Here is a link that might be useful: Some basic care info


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Center Update!
Originally published on March 17, 2015
University of Colorado Professor Patty Limerick will review nearly four decades of service as University Fool and reflect on the value of humor on April Fools' Day. On Wednesday, April 1, at 6:30 p.m. in the Wittemyer Courtroom of the Wolf Law Building on the Boulder campus, the history professor and Official University of Colorado…
Original article from The Denver Post
Originally published on 03/14/2015
By Patty Limerick
In a long overdue tribute, I write in praise of bus drivers. In Boulder, the express bus to Denver stops four blocks from my house. To put this in another way, I walk four blocks to get to Denver's downtown, a state of affairs that stretches the powers of the adjective "convenient." Without a moment's…
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As a four-year old, I took my first international flight in the early 1970s on a flight to Singapore from Bombay (and yes, my birth certificate will always say Bombay, not Mumbai). That trip inspired my lifelong fascination with airplanes and travel. I've been fortunate to have lived, been educated and worked in cities such as Bombay, Bangalore, Jakarta, Daytona Beach, Chicago and Atlanta. My interest in companies that "connect the world" shaped my choices and a career that has included working for the world's largest airline, the world's largest aircraft manufacturer, and now, a global leader in logistics and transportation solutions.
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To Register for a retreat, please click "More Info" for the retreat of your choice.
To open .pdf flyers located on the info windows, you will need Acrobat Reader. It is a free download that you can get here.
2015 Dates are at bottom
of chart. I know it's backwards, please forgive. (2014 dates hold the places for retreat dates in 2016.) Can't find a retreat in your area? Contact us and let's start one together!


text: |The CLASS Lesson Planner was designed to meet the particular needs of home educators. It thoroughly equips busy parents with practical help in managing their home and school. This planner is packed with suggestions for developing lesson plans, organizational techniques, and forms that permit the homeschooler to be more efficient in school administration and the creation of permanent records. Type: Paperback () Category: > Home Schooling ISBN / UPC: 9781930092136/0012059307 Publish Date: 7/1/2000 Item No: 144879 Vendor: Christian Liberty Press


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Tag Archives: SYTYCD
10 Seasons Later: Where are America's Favorite Dancers?
What can Amy and Fik-Shun expect now that they're officially the winners of "So You Think You Can Dance" Season … Continue reading
Reality TV Secrets Revealed
If you're anything like us, you're probably glued to the screen anytime a reality dance show is on. Then you … Continue reading
Happy Wedding Day, tWitch and Allison!
Today's the day: "So You Think You Can Dance" All-Stars Stephen "tWitch" Boss and Allison Holker are getting married! And … Continue reading
Go Behind the Scenes with Amy and Fik-Shun
Making it to the Top 20 of "So You Think You Can Dance" is really, really hard, so most will … Continue reading
The Power of Two
On "So You Think You Can Dance" Season 10, Amy Yakima and Du-Shaunt "Fik-Shun" Stegall had no shortage of magical … Continue reading
Karate Cole Returns as Bruce Lee
I hate goodbyes, which is why I have a really hard time when my favorite dancers get eliminated from "So … Continue reading


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Sprinklr Launches Experience Cloud And Announces New Funding To Surpass $1 Billion In Valuation
Sprinklr announced today its latest round of funding and the introduction of Experience Cloud™. An additional investment round of $46 million brings its total venture funding to $123.5 million. Sprinklr now has a valuation of over $1 billion. The company also launched Experience Cloud, an integrated technology that read »Stan Phelps, Contributor


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Can some one ID this?
Also any others similar to this in white, tight rose-like petals?
Here is a pic of Mother's Day peony which looks somewhat like your pic. Nick Shaylor is also roselike but it may open blush and have some red specks
Sorry, I meant Mother's Choice Peony.
Mother's Choice was my initial thought, too.


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I am: A Young Person | An Education Professional | A Corporate | A former Brokerage candidate
What is the City of London Business Traineeship Programme?
A unique opportunity for talented young Londoners to gain real experience, real responsibility and real pay after their sixth form studies.
With more than 100 prestigious opportunities across banking and the financial services, IT, insurance, legal and business administration sectors there are a wide variety of placements available. The placements are between 6-13 weeks and are paid at the going rate for that job.
This is not about work-shadowing - this will be a real job.
Am I right for the programme?
To be eligible for this programme you need to be:
These are strict criteria set by the programme funders. All candidates will be required to provide evidence of the above in person before they can be considered for paid placements.
If you meet some, but not all, of the criteria above, there are many other opportunities that the Brokerage may be able to offer you and you can still register with us.
Candidates for the City of London Business Traineeship Programme should also be:
Our commitment to you:
Once you have registered with us, we will:
Joining the Brokerage Pathway will also provide access to further opportunities throughout university and beyond, and we also have many opportunities for students who are interested in alternatives to university.
How do I register?
I'm ready to apply!
Please double check you meet the eligibility requirements above, then let's get started:
The City of London Corporation is a diverse organisation with three main aims - to support and promote the City as a world leader in international finance and business services; to provide the highest quality local government services for the Square Mile; and to provide valued services to London the nation as a whole.
The first and third aims are underpinned by the City Corporation's commitment to support the regeneration of its neighbouring communities. The City of London shares its borders with some of the country's most deprived boroughs where unemployment is high, despite the considerable employment opportunities in the City.
The City of London Business Traineeship programme brings together these two aims: help the City to attract high calibre, well motivated staff ables to meet its skills needs, whilst also looking to local sources to attract future members of the workforce.
The Brokerage Citylink has delivered the City of London Business Traineeship programme on behalf of the City of London Corporation since 2000. The programme is fully funded by the City Corporation.
Disclaimer and privacy:
800 volunteer hours were donated to our programmes in 2013
3,400 students visited a workplace in the City or Canary Wharf in year
Tell me more facts


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Message left on Rosalind's Facebook account Ros, I am starting an affiliate global network site, and we are promoting you and the Superaffiliatehandbook. We are excited about it. Thank you for all your guidance, I think you will be real impressed with the site, it's almost done. Regards, Adam Halem … [Read more...]
Thank you for all your guidance
An excellent source of reference for novices
Message left on Rosalind's Facebook account Hi Rosalind, Glad that I found you. Just wanna to tell you that your super affiliate handbook is an excellent source of reference for novices. Loh Chee Mun … [Read more...]
"genuine value and a very good read…"
This comment about the Super Affiliate Handbook was posted to our Support Desk... Hi Rosalind, It's very refreshing to purchase an e-book online which is of genuine value and a very good read - which yours is. ~ John Key … [Read more...]
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Comment Posted to RosalindGardner.com on April 1st, 2008 at 3:51 pm Love your blog Ros and your handbook is starting to look tattered by constant review. ~ Pete Safe … [Read more...]
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This is Karen's review of the Super Affiliate Handbook. They all do it. Did you know that? Who? All the top earners in the internet marketing industry, that's who. Sure, they have their own products. You may have purchased some already. But, without a doubt, all of them earn a substantial portion of their online income from affiliate marketing. Affiliate marketing simply means you … [Read more...]


text: I wish there was a rating for "Good". It was better than average, but not quite "Very Good". OK, I'm prejudiced because I live in Bangkok. I know good Thai food. This it it! Having Thai food in the US can be a real hit or miss proposition. My experiences with Thai food in the US really run the... read more


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Property Details
Condo, 2 Bedrooms, 2 Baths, 4 Sleeps
Vacation Rental Description
For April 1 to December 31: Owner prefers longer rentals.
For 2015: Three month minimum January 1 to March 31.
Enjoy this lovely second floor unit with a spectacular view of
community pool, shuffleboard court and Champs Golf Course at Palm
Aire. Fully furnished with 2 bedrooms/2 bathrooms; master bedroom
king-sized bed, walk-in closet and very large shower plus vanity
dressing area. Second bedroom with twin beds, large closet and
adjoining shower/tub combination bathroom. Well-equipped eat -in
kitchen has refrigerator/freezer, microwave, full electric stove,
An open living/dining room with cathedral ceiling flows into a
glassed/screened lanai with a relaxing view of community pool
(heated)/shuffleboard and clubhouse as well as as a sweeping view of
the Champs golf course.
Located on Timberlake Drive in the Woodland Green complex of Palm
Aire Country Club off University Parkway, with easy access to I-75
well as downtown Sarasota. Within 20-30 minutes: Siesta Key, Lido
Beach, St. Armand�s Circle, Longboat Key, Ringling Museum, Van Wezel
Performing Arts Center, Mote Marine Aquarium, Sarasota Opera,
Theatre, Asolo Theater and many fine restaurants. Shopping for
essentials (groceries, etc. a very short 5 or 6 minute drive) as
as an array of malls and outlet malls. Sarasota is known as
cultural capital and abounds with an exceptional variety of art,
music, theater and lecture venues. For the sports enthusiast there
convenient public golf courses nearby as well as tennis courts and
outstanding YMCA (3) in Sarasota/Bradenton area. Public libraries
outstanding and easy to access for visitors.,
About the Owner
Guestbook comments from the owner
Clean, efficient and a great view. Pool very handy--enjoyed it very much and strongly recommend this unit. If the Cincinnatti Reds were not moving to Arizona, I would return. Owners were accessible and very helpful in suggestions the sites of Sarasota!
0 Reviews
Be the first to review this listing!
Activity and Interests
Activities and Attractions
In addition to those mentioned above, Anna Maria Island, Sarasota
Ballet, Marie Selby Botanical Gardens, Myaka State Park, West Coast
Florida Symphony Orchestra, Golden Apple Dinner Theater, New College
of the University of South Florida (with many lectures open to
public), Sarasota Institute of Lifetime Learning, Selby Public
in downtown Sarasota. Busch Gardens and Disney/Sea World, Bok Tower,
and many other attractions within a 1 to 2 hour drive. Tampa is an
easy one hour drive.
Rental rates
- Monthly Rate: $1350 - $3200
Vacation Rental Rates
December thru April: $$3200 for one month; $3100 per month for two months; $3000 per month for 3 or 4 months. Owner prefers a minimum of three (3) months rental, December/January thru March/April. Longer rentals late fall to early spring also welcomed.
Off-Season rates: May thru November: $1350 for three months or more; $1500 for two months or less. Longer rentals preferred.
Condo Association Fee, Required: $100.00; State and Local Resort Taxes: 12%, as of May 2011.
All inquiries to: Toyia Youtzy, Property Manager Leasing Agent, Jennette Properties, c/o 5899 Whitfield Avenue, Sarasota, FL 34243.
Owner prefers longer rentals and will consider discount on a 3 to 6 month rental. YEARLY RENTALS WELCOME: 2013 BEGINNING APRIL 1+
Additional Rate Information:
Security Deposit: $1000 (contact Toyia)
Cleaning Fee: $100
Application Fee: $100
State and Local Taxes: (12%)
Minimal Rental: 30 days beginning the first of the month (required by condo association) During winter season owner prefers three (3) month rental: January 1 thru March 31. Longer rentals than 3 months are very preferable.
- 12
- Available
- 12
- Unavailable
- 12
- Today
Property Type
- condo
- Family
- Air Conditioning
- Internet
Pool / Spa
- Outdoor Pool
- non smoking only
- pets not allowed
Location Type
- Golf Course View
- 2 Bathrooms
- Bathroom 1 - toilet, shower
- Bathroom 2 - toilet, combination tub/shower
- 3 Bedrooms, Sleeps 4
- Bedroom 2
- Bedroom 1 - 2 king
- Bedroom 2 - 2 twin/ single
- Vacation Rental Amenities Condo unit is decorated in casual comfortable style. Floor plan is bright and open; central a/c ; free local telephone service; cable tv with dvd; washer/dryer in unit for your convenience. Internet service via Verizon DSL or Comcast available. Electric utilities provided up to $75 per month Additional amenities include: linens, towels, DVD, high speed internet connection (see above), iron and ironing board, laundry basket, vacuum cleaner, cleaning equipment, coffee maker, kitchen utensils, table settings, electric mixer, flatware and dinnerware for 8; cups/glasses; ice maker; mixing bowls, blankets; pillows. Sorry, no smoking, no pets,. No children unless visiting for a short period (one week or less).


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- Admissions
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WILSON, N.C. — Please join the Friends of Visual Arts at Barton College for the upcoming Winter Lecture featuring Ben Owen III. His lecture is titled "An Owen Tradition and Transition in Clay," and the event will be held in the Barton Art Galleries in Case Art Building at 6:30 p.m. on Thursday, Feb. 23. There is no charge for the program, and the community is encouraged to attend. Refreshments will be served.
He is a potter from Seagrove. His forefathers came to North Carolina from England as early as the late 1700s to ply their craft and furnish storage jars and other utilitarian wares for the early settlers. Owen's grandfather, master potter Ben Owen, Sr., admired early oriental pottery displayed in museums and collections, and he translated those works into his own style of pottery.
Ben Owen III studied pottery as an apprentice with his grandfather and later at East Carolina University. Like his grandfather, Owen's pottery reflects a foundation of traditional design as well as oriental translations.
For additional information about this program, please contact Bonnie LoSchiavo at 252-399-6477 or email: firstname.lastname@example.com.
Questions? Contact Kathy Daughety, director of public relations, at 252-399-6529 or email: firstname.lastname@example.com
Recent Posts
- The Honorable Sidney S. Eagles, Jr. Slated to Speak at Barton College's 113th Commencement on May 17 March 24, 2015
- "Walking into April" Poetry Day Scheduled for Saturday, April 11 March 24, 2015
- Friends of Hackney Library Presents "An Evening with Elaine Neil Orr" on April 7 March 24, 2015
- Charles W. Calhoun to Present Heritage Lecture on March 31 March 18, 2015
- FOVA Art Lunch and Lecture Series on March 26 Features N.C. Connection March 18, 2015


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Ralph Lauren Polo 3082/S Safari
. Price in USD is for your reference only, payment will be settled in US Dollars.
- Colour code: 924573
- Size: 61 mm / 13 mm / 140 mm
Frame colour: Dark gunmetal, vintage effect
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Crazycar! Here is the link!!
Submitted by Liberty_Belle on Thu, 02/26/2009 - 17:25. Permalink
I will check it out! Looks like fun!
"I truly wish that real life would no longer surpass the worst excesses of my nightmarish imaginings... Arthur Silber **
"I think we are living in a world of lies: lies that don't even know they are lies, because they are the children and grandchildren of lies." ~ Chris Floyd


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SNS St Louis 1850 - Dardenne Prairie (SV 060574)
7909 Hwy N
Dardenne Prairie, MO 63368
Map |
Driving Directions
(636) 561-4650 - Main
(636) 561-8450 - Pharmacy
Store Hours:
5 am - 1 am, 7 days a week
Pharmacy Hours:
Mon - Fri: 9 am - 9 pm
Sat: 9 am - 6 pm
Sun: 10 am - 4 pm
Holiday Hours:
Easter 7 am - 7 pm
Pharmacy Holiday Hours:
Easter Closed
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By Catholic Online (NEWS CONSORTIUM)
1/17/2014 (1 year ago)
Catholic Online (www.catholic.org)
Every home has a kitchen - but many people visit restaurants several times a week. So it is with the e-book, an electronic tablet that aids in the reading of the printed word. More than half of all Americans claim to have them - but fear not for the printed word, as traditional books are just as popular now as ever.
By Catholic Online (NEWS CONSORTIUM)
Catholic Online (www.catholic.org)
1/17/2014 (1 year ago)
Published in Technology
Keywords: E-book, printed word, book sales, Audiobooks
LOS ANGELES, CA (Catholic Online) - According to a recent study, 28 percent of Americans read at least one e-book in 2013 up from 23 percent the year earlier, according to a new survey of more than 1,000 adults from the Pew Research Center.
Surprisingly, the percentage of people who read print books increased as well with 69 percent claiming they had read at least one print book, a rise of four percent from the previous year.
Join the worldwide fight against malaria by going here --
"Though e-books are rising in popularity, print remains the foundation of Americans' reading habits. Most people who read e-books also read print books, and just four percent of readers are 'e-book only,'" the study's authors said.
Audiobook listeners, those who listen to books that are read aloud on tape or CD have the most diverse reading habits overall the study found. Fewer print readers consume books in other formats.
"Overall, 50 percent of Americans now have a dedicated handheld device-either a tablet computer like an iPad, or an e-reader such as a Kindle or Nook-for reading e-content," the center said. "That figure has grown from 43 percent of adults who had either of those devices in September."
The study shows 50 percent of respondents saying they have a tablet or stand-alone device such as Amazon.com's Kindle, up from 43 percent in September. Only around four percent read e-books exclusively.
While sales for e-books are growing, but have leveled off over the past couple of years. They're believed to comprise 25 to 30 percent of the general trade market, with commercial fiction especially popular for e-books.
"The proportion of Americans who read e-books is growing, but few have completely replaced print books for electronic versions," Pew says.
Pope Francis calls for your 'prayer and action'...
St. Joseph of Cupertino
St. Barbara
St. Jude
St. Matthew
St. Francis of Assisi
St. Gerard
St. Joseph
St. Brigid of Ireland
St. George
St. Clare
St. Anthony
St. Christopher
St. Mark
St. Ann
St. Benedict
St. Florian
St. Isidore the Farmer
St. John the Baptist
By Hannah Raissa Marfil (NEWS CONSORTIUM)
Facebook's chief technology officer, Mike Schroepfer promised that the Virtual Reality (VR) program will come into life within the year. The Oculus headset, which was on their top secret list before, was announced to be available soon, but the exact release date is not ... continue reading
By Hannah Raissa Marfil
The number of young people being admitted for mental treatments since 2010 has rapidly increased. Julie Lynn Evans, a psychotherapist for over 25 years now, is grateful for the additional funding being sent into mental health services, but she believes the dilemma ... continue reading
By Catholic Online (NEWS CONSORTIUM)
A mainstay of United States military defense, stealth bombers have been around since the Seventies. The Air Force's aging fleet is now ready for an expensive makeover. The Pentagon intends to develop a high-priority, super-classified, next-generation bomber. ... continue reading
By Hannah Raissa Marfil (NEWS CONSORTIUM)
Classic toy doll, Barbie, has been reinvented after the makers, Mattel received numerous requests for a Barbie doll that kids can talk to, according to a spokesperson of the toy company. Mattel's response is WiFi connected "Hello Barbie" that comes with an installed ... continue reading
By Abigail James (NEWS CONSORTIUM)
New gene-editing techniques are being improved and could soon eliminate inherited diseases from future generations by modifying the DNA of human egg cells. LOS ANGELES, CA (Catholic Online) - Although the idea of editing chromosomes in human eggs or sperm is feared, ... continue reading
By Hannah Raissa Marfil (NEWS CONSORTIUM)
A hidden camera disappeared just after an hour of being discovered at a Denver local post office, Fox31 Denver reported. People became alarmed that they are being watched as they drop-off their mails with the possibility of the camera collecting their facial features ... continue reading
By Hannah Raissa Marfil (NEWS CONSORTIUM)
By participating in the Ultimate Selfie Campaign (#ultimateselfiecampaign), people can now have millions of people across the United States see their selfie or favorite photo on digital billboards, while helping charities with a $25 donation. The project was an ... continue reading
By Catholic Online (NEWS CONSORTIUM)
While Apple remains unusually successful, there are already naysayers lining up to predict that the company's forthcoming "Smartwatch" will be a flop. Many details about the new gadget remain under wraps. Questions remain about the watch's price, the battery ... continue reading
By Hannah Raissa Marfil (NEWS CONSORTIUM)
"Pee Power" is what the people are calling this strange innovation. British students and researchers, from the University of the West of England and the OxFam global aid agency, have invented a mode in which light bulbs can be powered by urine. The University has ... continue reading
By Catholic Online (NEWS CONSORTIUM)
In the event the dead return to life and begin to cannibalize the living, turning them into hordes of the shuffling undead, theoretically - there would be few options. Researchers at Cornell University offer a practical bit of advice should this happen - head ... continue reading


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Additional file 3.
Universal orthologues used to construct the distance based phylogeny. The list of universally distributed genes used to construct the phylogeny are listed here; the top row indicates the E. coli orf. Below the E. coli orf, the orthologous reading frame in each genome is listed.
Format: TAB Size: 405KB Download file
Silander and Ackermann BMC Research Notes 2009 2:2 doi:10.1186/1756-0500-2-2


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penguu(8)June 25, 2013
I have a botanical/historical question.
Crusea, Antiphytum, Cordia are all named XX saucerflowers. Does "saucerflower" refer to the shapes of the flowers? Crusea in particular doesn't look very saucer-like to me at all! Did one plant become strongly identified with the name saucerflower and others get compared to it, like how plantain and lily shows up in a lot of common plant names?
Where would I look up this kind of information?


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Page 1
Matrix Gla-protein:The calcification inhibitor in need of vitamin K
Leon J. Schurgers, Ellen C. M. Cranenburg, CeesVermeer
VitaK and Cardiovascular Research Institute (CARIM), Maastricht University, Maastricht,The Netherlands
Among the proteins involved in vascular calcium metabolism,
the vitamin K-dependent matrix Gla-protein (MGP) plays a
dominant role.Although on a molecular level its mechanism of
MGP is a potent inhibitor of arterial calcification.Its pivotal im-
portance for vascular health is demonstrated by the fact that
there seems to be no effective alternative mechanism for calcifi-
cation inhibition in the vasculature.An optimal vitamin K intake
is therefore important to maintain the risk and rate of calcifi-
cation as low as possible.With the aid of conformation-specific
Matrix Gla-protein, vitamin K, calcification, cardiovascular dis-
ease, oral anticoagulants
antibodies MGP species in both tissue and the circulation have
been detected in the healthy population, and significant differ-
Using ELISA-based assays, uncarboxylated MGP (ucMGP) was
demonstrated to be a promising biomarker for cardiovascular
calcification detection.These assays may have potential value for
identifying patients as well as apparently healthy subjects at high
risk for CVD and/or cardiovascular calcification and for moni-
toring the treatment of CVD and vascular calcification.
Thromb Haemost 2008; 100: 593–603
Theme IssueArticle
Correspondence to:
Dr. L. J. Schurgers
VitaK, Maastricht University
Universiteitssingel 50
6200 MD Maastricht,The Netherlands
Tel.: +31 43 3881680, Fax: + 31 43 388 4159
E-mail: firstname.lastname@example.com
Received February 14, 2008
Accepted after minor revision July 2, 2008
Prepublished online September 5, 2008
Matrix Gla-protein (MGP) is a small secretory protein that can
undergo two types of posttranslational modification: γ-gluta-
first described in 1983 by Price et al. who purified it from the
mately 14 kD protein contains five unusual amino-acids desig-
nated as γ-carboxyglutamate (abbreviated as Gla), and therefore
the protein was designated as matrix Gla-protein (Fig. 1). Soon
after its discovery in bone, MGP synthesis in cartilage, lung,
heart, kidney, arteries and calcified atherosclerotic plaques was
confirmed (1–3).The mature protein consists of 84 amino-acids
and has a theoretical PI of 9.7. Of the nine glutamate residues
only five can be γ-carboxylated in a vitamin K-dependent reac-
tion, and three of its five serine residues can be phosphorylated
into phosphoserine (abbreviated as Pser). The MGP gene is lo-
cated on chromosome 12 (p13.1-p12.3), consists of four exons
and three large introns and has a length of 3.9 kb. It contains
AP1 and AP2 and cAMP-dependent transcription factors. At
VSMC whereas retinoic acid down regulates its expression (4).
The best studied posttranslational modulation of MGP is
gamma-glutamate carboxylation. Gla-residues are formed in a
vitamin K is to provide the energy to drive the carboxylase reac-
tion. The Gla-residues formed are negatively charged and pro-
common characteristic of all known members of this protein
carboxylase is determined by a pro-sequence located immedi-
ately at the N-terminal site of the protein. In most Gla-proteins
the pro-sequence is cleaved off during maturation; MGP is the
Phosphorylation, the other posttranslational modification in
MGP, may take place at serine residues in positions 3, 6 and 9
serine phosphorylation is the tandemly repeated Ser-X-Glu se-
nase (4, 7). The function of serine phosphorylation is not pre-
cisely known, but recent data suggest that it plays a role in regu-
lating the secretion of proteins into the extracellular environ-
© 2008 Schattauer GmbH, Stuttgart
New vitamin K-dependent proteins
Page 2
Schurgers et al. Matrix Gla-protein and vascular calcification
lar smooth muscle cells (VSMCs) via the secretory pathway,
whereas the non-phosphorylated MGP appears in the cytosol,
and is thus not secreted (7).
The fat-soluble vitamins A and D may modulate MGP ex-
pression. Retinoic acid is a regulator of chondrocyte maturation
and mineralization (8). Its effect on mRNA expression levels of
MGP is cell type-dependent: in fibroblasts, chondrocytes, os-
teoblasts, and type II pneumocytes, retinoic acid upregulates
MGP mRNA expression (9, 10) whereas in kidney cells and
VSMCs, retinoic acid downregulates MGP expression (11, 12).
1,25(OH)D3was shown to increase MGP expression in vitro in
calcification, most likely due to an effect on calcium-metab-
Functions of MGP
Although the precise molecular mechanisms of MGP function
are not known, accumulating data demonstrate its major role in
the inhibition of soft-tissue calcification. The first clues for a
Gla-protein being involved in the inhibition of tissue calcifi-
farin (16). These animals developed massive cartilage calcifi-
cation, notably in the epiphyses and facial bones, leading to im-
paired growth, maxillonasal hypoplasia and reduction in the
of MGP in cartilage that it was recognized that the cartilage cal-
its discovery, it was thought for many years that the importance
that its main function is the inhibition of medial calcification of
the arteries: MGP-deficient animals all died within six to eight
tunica media, resulting in rupture of the large arteries (19).The
tite, thus mimicking bone mineralisation. Using histochemical
techniques, the authors demonstrated that the arterial calcifi-
cation was associated with the differentiation of VSMCs into
chondrocyte-like cells.A mechanism explaining the strong cal-
cification inhibitory activity of MGP was put forward by Price,
who suggested that MGP binds tightly to the crystal nuclei thus
preventing further growth (20). Inhibition of the differentiation
of VSMCs into chondocyte- and osteoblast-like cells may be a
in MGP-deficient mice by demonstrating a loss of smooth
transcription factor cbf1a/Runx2 and the osteogenic protein os-
teopontin (21). The ability of MGP to keep VSMCs in the con-
tractile phenotype may be accomplished by binding to the bone
of the transforming growth factor-beta (TGF-beta) superfamily,
expressed in human atherosclerotic lesions (24). Wallin et al.
demonstrated that only the carboxylated form of MGP binds to
that MGP blocks the osteo-inductive properties of BMP-2 (25).
This inhibitory function is further supported by work of Shana-
of arteries from diabetic patients with Mönckeberg's sclerosis
than in normal vessels (26).Via its C-terminal region, MGP can
also bind to the extra-cellular glycoprotein vitronectin, which is
minal part of MGP is hydrophobic and does not contain Gla- or
Pser-residues, which are all present in the more hydrophilic
Figure 1: Matrix Gla-pro-
tein (MGP) is a small 84aa
vitamin K-dependent pro-
tein.Although its 14 kD size,
it can undergo two posttrans-
lation modifications: at posi-
tion 3, 6, and 9 the serine resi-
dues can be phosphorylated by
a Golgi-casein kinase, and at
positions 2, 37, 41, 47 and 52
the glutamate residues can be
γ-carboxylated (117).
New vitamin K-dependent proteins
Page 3
Schurgers et al. Matrix Gla-protein and vascular calcification
ized that MGP's binding to vitronectin results in a concentration
of calcification-inhibitory activity in the milieu surrounding the
elastic fibers, thereby protecting them from mineralization.
Formation of matrix vesicles (MV) and apoptotic bodies
(AB) is thought to precede and/or initiate arterial calcification.
in the initiation of calcification (28).The physiological function
nidus of calcification in cartilage. Also in the vessel wall, both
MV and AB are relatively common, notably in atherosclerotic
plaques (29, 30), arterial injury (31) and Mönckeberg's sclerosis
cellular nodules, containing a high number of AB. MGP ex-
pression is highest in this phase, suggesting an association be-
systems that VSMC derived MV and AB both contained MGP
which is thought to limit the rate of calcification (34).
The specific knock-in expression of MGP in VSMCs of
MGP-deficient mice completely rescued the calcification phe-
notype (35). In the same article the authors also expressed MGP
in the liver of MGP-deficient mice, resulting in high levels of
circulating MGP. However, the elevated systemic levels of MGP
had no effect on inhibition of arterial calcification implying that
MGP inhibits calcification by acting locally within its tissue of
coding for MGP – predicting a non-functional protein – cause
the Keutel syndrome (36), a rare disorder characterized by ab-
normal cartilage calcification and peripheral pulmonary steno-
revealed extensive arterial calcification (38).
Arterial calcification
Until a decade ago, calcification of arteries was thought to be a
passive, clinically irrelevant process, resulting from a high cal-
cium x phosphate product, inflammation, lipid accumulation or
diabetes. However, during recent years it has become increas-
ingly clear that vascular calcification is an active process and an
important, independent pathology that is strongly associated
with increased risk of cardiovascular morbidity and mortality
(39–41). Clinically, vascular calcification causes stiffening of
the vascular wall, which may result in decreased arterial com-
pliance, development of left ventricular hypertrophy and de-
creased coronary perfusion leading to an increased risk of fatal
complications (42, 43). Calcification is common in the elderly
population, and in patients suffering from diseases such as
chronic kidney disease (CKD), diabetes, aortic stenosis, and
atherosclerosis (44). Therefore, a lot of efforts have been di-
arterial calcification is reversible (45–48), demonstrating that
also the regression process is an actively regulated process. In
fect (49, 50).
CKD patients have the highest incidence of arterial calcifi-
apparently healthy population (51, 52). Moreover, moderate to
hemodialysis (53, 54). Recently, it was shown that vitamin
K-status in CKD patients is low (55). Circulating vitamin K lev-
els were measured and reported that some 30% of the haemo-
dialysis patients had sub-clinical vitamin K-deficiency.The au-
thors discussed the possibility of giving these patients extra vit-
amin K to reduce the risk for cardiovascular events (55). Addi-
amin K antagonists, which is regularly prescribed in these pa-
Together with the additional immunohistochemical evidence of
high levels of uncarboxylated MGP (ucMGP) present in calci-
K intake as a novel treatment option for cardiovascular calcifi-
cation (see also below). The first clinical studies in dialysis pa-
tients are in progress.
Factors affecting MGP activity
Vitamin K / warfarin
It has been known for a long time that women receiving anti-
coagulant therapy with vitamin K antagonists (coumarin deriva-
tives) during the first trimester of pregnancy are at risk of de-
livering children with a syndrome characterized by nasal hypo-
plasia, depression of the nasal bridge and punctuate calcifi-
cations in the axial skeleton, proximal femurs and calcanei (58).
syndrome), and the abnormalities were first believed to be
caused by haemorrhages in the developing fetal cartilages with
soon recognized that this was unlikely, since clotting factors
were known to be absent during the first trimester of pregnancy
(58, 61). Similarities between the facial and skeletal abnormal-
ities seen in warfarin embryopathy and the fetal phenytoin (hy-
may underlie these abnormalities (58, 62). This was confirmed
by Pauli et al. who described a congenital deficiency of the
ling of vitamin K), causing prenatal vitamin K deficiency, and
resulting in a similar phenotype (63, 64). In later years it was re-
ported that also dietary vitamin K-deficiency results in com-
ably similar to the bone and cartilage defects observed in warfa-
rin-treated rats (16). The same animal model provided the first
evidence that impairment of MGP function results in vascular
calcification (20). It was found that within two weeks of warfa-
rin treatment, the elastin fibres in the tunica media were signifi-
theMGPnullmiceinwhichMGP cannot becarboxylated,since
the glutamate residues in the Gla-domain were mutated into as-
partate; in this way it was demonstrated that only carboxylated
MGP (cMGP) exhibits anti-mineralization properties (35). Vit-
amin K antagonists are frequently used to prevent thrombosis in
New vitamin K-dependent proteins
Page 4
Schurgers et al. Matrix Gla-protein and vascular calcification
patients at increased risk for thrombosis (70).Treatment periods
range from several weeks to many years, even often life-long
(71). After demonstration in animal models that vitamin K an-
tagonists induce vascular calcification, studies in two indepen-
dent populations revealed that indeed treatment with coumarin
derivatives induces excessive calcification of the coronary ar-
teries and the aortic heart valve (72, 73). Schurgers et al. com-
pared valvular calcification in patients receiving oral anticoagu-
tients not on oral anticoagulation (72). Histopathological evalu-
ation of the valves from the patients who had received oral anti-
coagulation showed partial or total valve destruction induced by
amorphous calcified deposits. Quantification of the calcium
contents of the aortic valves showed a statistically significant
difference between valves from those who had never received
oral anticoagulant treatment and those who had received this
treatment. These data were confirmed by Koos et al., who used
multislice spiral computed tomography (CT) to quantitate the
agulant treatment (73). It was found that these patients had in-
creased coronary calcification compared to patients without
anticoagulation treatment (Agatston score 1,561 and 738, re-
spectively). The present policy is opposite, however: large
numbers of cardiovascular disease (CVD) patients receive anti-
coagulant therapy with vitamin K antagonists, which increases
their calcification tendency. The data described above suggest
that – if possible – other forms of anticoagulation (specific pro-
thrombin or factor-X inhibitors) should be employed, preferably
creases CVD in parallel. Together, these data demonstrate a hi-
therto unrecognized adverse side-effect of coumarin derivatives
botic treatments for patients.
Vitamin K comprises a family including vitamin K1(phyllo-
quinone) and vitamin K2(menaquinones). The mechanism of
vitamin K1is believed to be most important for activation of he-
patic clotting factors whereas K2also is important for proteins
synthesized in extra-hepatic tissues such as the vasculature.
additional properties, including apoptosis and cell-cycle arrest
and anticancer properties (74, 75), inhibition of the synthesis of
prostaglandin E2 (PGE2) (76), osteoclast apoptosis (77), and
teoblastic markers (78). Recently, it was shown that vitamin K2
could also down regulate osteoprotegrin and increase DT-dia-
phorase, implicating that vitamin K2is an anti-calcification
component in the vessel wall (79). For a more extensive review
on the gene regulatory functions of vitamin K2, see Shearer ar-
ticle, this volume beginning on page 530.
The question of whether high vitamin K-intake is protective
based study among participants of the Rotterdam Study. It was
versely correlated with cardiovascular calcification and cardio-
K2intake had about 50% reduction in both aortic calcification
and cardiovascular mortality and 25% decreased all-cause mor-
tality. In a clinical intervention study in which 78 women be-
tween 55 and 65 years of age received either vitamin K (1 mg/
day) or placebo for three years, vascular characteristics were as-
sessed (elasticity and distensibility) (80). In subjects in the
placebo group vascular elasticity had decreased by 10–13%,
which is consistent with the normal decrease during the time-
period of three years; in the vitamin K group, however, vascular
Theconceptofcalcification inhibition byhighvitamin Kin-
take was confirmed in experimental animals (81). In this model
the efficacy of vitamins K1and K2in preventing arterial calcifi-
cation was compared. It was found that K2completely inhibited
tissue calcification, whereas a similar or even an eight-fold
higher dose of K1had no measurable effect.To fully understand
this model it is important to know that vitamin K1can be con-
verted into MK-4 via MK4-O, but that warfarin blocks the con-
version of MK4-O into reduced MK4, which is the active cofac-
long chain K2vitamins such as menaquinone-7, have lower KM
values for the enzyme γ-glutamyl carboxylase, demonstrating
Additionally, recently Wallin et al. showed that specifically K2
acts as an anti-calcification component in the vessel wall by in-
creasing the gene expression with a 4.8-fold higher specific ac-
tivity of DT-diaphorase, an enzyme of the vitamin K-cycle (79).
The same animal model was used to study the effect of high vit-
amin K intake on potential regression of arterial calcification
(47). Whereas rats receiving the standard chow (control) had
warfarin treatment led to the accrual of calcium salts up to
12-fold above the baseline values. During the following six-
week period warfarin treatment was stopped and the animals re-
ceived either standard chow or standard food fortified with a
high dose of vitamin K1or K2. It was shown that once calcium
deposits had formed, the accrual of calcium salts in the vascula-
ture increased linearly after the warfarin diet had been replaced
however, the process of calcification was not only stopped, but a
significant fraction (some 40%) of the previously formed cal-
cium salts had been removed within six weeks. This effect was
had decreased, suggesting a role of activated MGP in the regres-
sion of calcified plaques.The fact that vitamins K1and K2had a
similar effect in this experiment may be explained by the very
by performing dose-response studies the efficacies of both vit-
amins may be compared in this model.
Carboxylase /VKOR
pendent clotting proteins (85, 86). Since only one gene encodes
for the enzyme, also Gla-proteins produced in extra-hepatic tis-
New vitamin K-dependent proteins
Page 5
Schurgers et al. Matrix Gla-protein and vascular calcification
sues are affected by this mutation. More recently it was shown
that patients with the γ-glutamate carboxylase mutation not only
presented with haemostatic disorders, but also with soft tissue
ticum (PXE)-like phenotype (87). Pseudoxanthoma elasticum is
an autosomal recessive multi-system disorder characterized by
dystrophic mineralization of soft tissues, including skin, eyes,
mutations in theABCC6 gene (ATP-binding cassette subfamily
C member 6), patients with the PXE-like syndrome harboured
cently demonstrated by two groups, showing that fibroblasts
from PXE patients almost exclusively produce the inactive
ucMGP, which is not able to block or inhibit calcification (89,
90). The very low cMGP production in pathological fibroblasts
compared to controls suggests these cells have a deficient vit-
amin K metabolism which may play an important role in the ec-
topic calcification in PXE.
The vitamin K-epoxide reductase (VKOR) enzyme is a cru-
cial enzyme in vitamin K metabolism and ensures the re-utiliz-
ation of vitamin K after it has been oxidized in the carboxylase
reaction. Because of this recycling, human vitamin K require-
vitamin K-epoxide in two steps: first to the quinone, and subse-
factor for γ-glutamate carboxylase. VKOR is also the target for
warfarin and related coumarin derivatives, which block the re-
cycling of vitamin K thereby decreasing the vitamin K-status.
Both vitamin K-epoxide and vitamin K quinone need to bind to
the VKOR before being reduced. Wallin et al. showed that the
enzyme DT-diaphorase inVSMCs is 100-fold less active than in
the liver.The cytoplasmic DT-diaphorase is capable of reducing
vitamin K quinones to their hydroquinone cofactors, and serves
as a rescue enzyme in case the VKOR is blocked by coumarin
(92, 93).Therefore, coumarin treatment has a detrimental effect
in the arterial vessel wall, by blocking vitamin K-metabolism
leading to impaired MGP. Moreover, the vitamin K binding site
inVKOR is thought to be close to the coumarin-binding site and
recently it was shown that the presence of variousVKORC1 ha-
plotypes correlates with arterial vascular disease (94).
Besides being a cofactor in the vitamin K-dependent car-
boxylation, KH2also possesses antioxidant activity (95, 96).
This is consistent with its high sensitivity to free radicals, which
may oxidize (and thus inactivate) KH2before it can take part in
the carboxylation reaction. Especially in the atherosclerotic
plaque, high levels of oxidized LDL are found, which may thus
contribute to a local vitamin K deficiency.
MGP as biomarker
amin K. MGP is a local inhibitor of vascular calcification and it
has been demonstrated that circulating MGP has no biological
function (35). However, circulating MGP may reflect calcifi-
sue and in the circulation, and the potential of circulating MGP
as a biomarker for cardiovascular calcification.
MGP in vascular tissue
MGP is synthesized at relatively low rate (2, 57, 97), most likely
because the need for calcification inhibition is low. However,
Shanahan et al. showed that in arteries of diabetic patients lower
levels of MGP protein were present than in normal vessels, sug-
gesting that low MGP levels might predispose for calcification
(26). High MGP levels have been detected in arteries with cal-
cification (2, 57, 97). This may originate from increased MGP
terial calcification (2, 57, 97), or increased subsequent adsorp-
tion to the calcium salt crystals.
With the development of conformation-specific antibodies,
enabling the detection of active, carboxylated and inactive, un-
carboxylatedMGP (cMGP anducMGP,respectively),itbecame
clear that specifically the ucMGP conformation accumulates in
atherosclerotic and calcified arteries (56, 57, 90). The cMGP
conformation was nearly absent in these arteries. These con-
formation-specific antibodies have proven their value for MGP
detection and studying vitamin K-metabolism in several animal
models. Wajih et al. demonstrated the processing and transport
of the different MGP conformations in cultured VSMCs (7). In
clearly presented by using conformation specific antibodies
against MGP. Sweatt et al. demonstrated that calcified arterial
lesions in aging rats contained elevated MGP levels, which was
uncarboxylated and not able to bind BMP-2 (56). Our group
UsedDirected against
moAb dpMGP
moAb pMGP
moAb ucMGP
moAb cMGP
Desphosphorylated MGP
Phosphorylated MGP
Uncarboxylated MGP
Carboxylated MGP
inactive MGP fraction
active MGP fraction
Table 1: Matrix Gla-protein antibodies. moAb = monoclonal
antibody;W =Western blot; I = immunoprecipitation; S = section;
E = ELISA.Antibodies available atVitaK Products BV (www.vitak.org)
Table 2: Possibilities of MGP ELISA's. Four single antibody com-
petitive assays can be developed, namely dpMGP, pMGP, ucMGP and
cMGP conformation.Also, antibodies directed against the C-terminal
part of MGP could be used to measure the total of MGP proteins.These
monoclonal antibodies are not available yet. Combinations of the con-
formation specific antibodies could result in several MGP sandwich com-
binations. Here we hypothesise that dp-ucMGP is the inactive fraction
whereas p-cMGP represents the active MGP fraction. More research is
needed to find out the exact role of the different MGP combinations.
New vitamin K-dependent proteins
Page 6
Schurgers et al. Matrix Gla-protein and vascular calcification
Figure 2:Vitamin K-dependent regulation of vascular calcifi-
cation.A)Vitamin K-sufficiency: In the case of sufficient vitamin K
supply (either via food or supplements) and in the absence of disease, all
MGP synthesised in theVSMCs is activated to prevent calcification: the
clearance of matrix vesicles (MV) and apoptotic bodies (AB) is sup-
ported by either macrophages and/or surroundingVSMCs. In this way,
the nidus for calcification is absent.There is no hydroxyapatite matrix in
the tunica media to bind to MGP.The fraction of MGP leaking into circu-
lation is the dp-cMGP and p-cMGP. B)Vitamin K-insufficiency:Vitamin K
insufficiency is present in subjects with sustained low vitamin K intake or
patients on vitamin K-antagonist (coumarin derivatives).The expression
of MGP is normal.The inactive MGP will lead to decreased clearance of
MV andAB.The negatively charged phospholipid-remnants have the ca-
pacity to nucleate calcium and phosphate and subsequently calcify in the
absence of the calcification inhibitory function of MGP.The phosphory-
lated ucMGP fraction will bind to the vascular calcification, and thus the
p-ucMGP is lowered.The fraction easily released in the circulation is dp-
ucMGP (this fraction has no or limited affinity for vascular calcium).Vit-
amin K-insufficiency (as deduced from inactive ucMGP species in the cir-
culation) is present in the majority of the apparently healthy population.
C) Calcification triggered by disease: In diseases leading to the shedding
of high numbers of MV andAB, calcification is triggered and the need for
New vitamin K-dependent proteins
Page 7
Schurgers et al. Matrix Gla-protein and vascular calcification
active MGP is high.Also in diseases with a balance in favour of calcifi-
cation, e.g. high calcium-phosphate product (ESRD), inflammation (lead-
ing to apoptosis), a high synthesis of MGP is needed to counteract the
nidus for calcification. In response, the demand for vitamin K increases.
In the majority of the population the intake of vitamin K is insufficient to
address this higher demand of vitamin K, required for the activation of
all newly synthesised MGP.Therefore, a major part will occur in the
ucMGP conformation, unable to stop or reverse calcification; MGP will
bind to the local vascular calcifications via the p-ucMGP conformation
which will be measured by the lower plasma p-ucMGP levels.The circu-
lating MGP fraction which has no or limited affinity of calcium (dp-
ucMGP) is high in this situation. D) High vitamin K-intake: Once calcifi-
cations are present, and dp-ucMGP is high, high intake of vitamin K
could be used as treatment option. In this way, all newly synthesised
MGP will be activated via the γ-carboxylation reaction.This will result in
dp-cMGP and p-cMGP.As the active MGP fraction will support clearance
/ regression of calcification the amount of calcification will reduce. In the
circulation, this will be reflected by a lowered dp-ucMGP level, demon-
strating a beneficial shift in the tissue.
New vitamin K-dependent proteins
Page 8
lesions which are rapidly formed in the arteries of rats during
treatment with warfarin. Additionally, it appeared that high vit-
amin K intake resulted in improved MGP carboxylation, regres-
sion of pre-formed calcifications and subsequent increased vas-
cular elasticity (47).The conformation-specific antibodies have
recently become commercially available, which will facilitate
the demonstration of their potential value as a diagnostic tool in
specimens of patients with cardiovascular disease (Table 1).To-
gether with expression levels of MGP, the activity-status of the
protein may help to understand the precise function of MGP in
the local inhibition of vascular calcification.
Circulating MGP
MGP can also be detected in the circulation with ELISA-based
techniques. The use of a circulating biomarker for CVD and/or
vascular calcification is an attractive possibility. Its value in the
diagnostic area might be the pre-screening of patients before
subjecting them to electron beam or multislice CT scanning.
cifications (98–100) but has the disadvantages of being expens-
ive and posing an increased cancer risk due to the radiation load
(101). The latter is especially important for regular follow-up
during treatment.The crusade for finding biomarkers represent-
ing or predicting vascular disease has led to the development of
(20, 102–104). Of these proteins, only the function of MGP can
be modulated, by either vitamin K or vitamin K-antagonists.
Circulating levels of MGP will depend on the rate of MGP syn-
thesis in vascular tissue, its secretion from VSMCs and sub-
sequent binding of MGP to calcified areas that may be present
MGP circulates. Mature MGP is highly insoluble and it is not
associated with a carrier. Full-length MGP has been purified
from the plasma of rats as a complex including calcium, phos-
phate, carboxylated MGP and fetuin (105). On the other hand,
kD protein (106).Additionally, it is likely that also a substantial
fraction of plasma MGP occurs as fragments.
MGP can undergo two posttranslational modifications: the
aminoacid sequence 3–15 with three serine (ser) residues which
can be phosphorylated, and aminoacid sequence 35–53 contain-
γ-carboxylglutamate (gla) (Fig. 1 andTable 1).These modifica-
set free in the circulation (Table 2). In the literature three assays
for circulating MGP have been described. All three tests de-
scribed are single antibody assays that do not discriminate be-
The first published assay is a single antibody ELISA using a
minal MGP aminoacid sequence 3–15 (107, 108). This assay
only measures non-phosphorylated MGP (dpMGP), and does
not discriminate between cMGP and ucMGP. It has been re-
ported the the dpMGP fraction is only a minority of the total
MGP produced (4). Using a proteomics approach, Wajih et al.
proposed that the phosphorylated fraction is secreted into the
extra-cellular environment, whereas the non-phosphorylated
form is only secreted as matrix vesicles or apopotic bodies (7).
Thus, non-phosphorylated MGP may predict the VSMC stress
locally. Increased levels of serum MGP were measured in pa-
tients with severe atherosclerosis and with type I diabetes melli-
tus using this assay (107).The same assay was used in collabor-
(EBCT) in subjects with suspected coronary artery disease, and
MGP was measured in serum samples from these subjects. The
serum levels of MGP were significantly lower in subjects with
CAC compared to those without CAC. Moreover, serum MGP
consistent with data obtained in experimental animals in which
significantly lower MGP levels were measured in animals with
massive arterial calcifications (20, 47). An explanation for this
lation of MGP synthesis.
is a radioimmunoassay using polyclonal antibodies directed
is not possible to discriminate between the different MGP con-
positive correlation between circulating MGP levels and coron-
ary heart disease risk factors (Framingham CHD risk score) in
correlated significantly with serum MGP levels. However, no
directed against the non-carboxylated MGP sequence 35–53 to
measure circulating ucMGP levels was described (106, 111).
between 1. full length MGP or fragments or 2. phosphorylated
MGP (pMGP) and dpMGP. The assay was validated in a wide
range of patient populations prone to develop arterial calcifi-
cation, including patients with atherosclerosis and renal dys-
function (106). All patient groups had significantly lower
ucMGP values than healthy subjects of comparable age. This
assay was particularly successful in identifying patients with
end-stage renal disease (ESRD) and calciphylaxis, a condition
characterized by extensive calcification of cutaneous arterioles.
MGP levels in these patients were almost without exceptions
aortic augmentation index (111). Moreover, in a well character-
tween circulating MGP levels and CAC scores measured by
MSCT (E. C. M. Cranenburg et al., submitted for publication).
These results could indicate that low MGP levels may be a
marker of active calcification.The low MGP levels in these pa-
tient populations could be explained by the accumulation of
ucMGP at sites of arterial calcification (14, 56, 57), suggesting
that ucMGP is not set free into the circulation.An additional ex-
ucMGP is in the p-ucMGP form and that phosphorylation alone
is sufficient for the binding of MGP to vascular calcifications
(Fig. 2C). Indeed, previously we found no correlation between
Schurgers et al. Matrix Gla-protein and vascular calcification
New vitamin K-dependent proteins
Page 9
0.385) (106). To interpret these data, one could speculate that
MGP is processed in a phosphorylated form, and that also the
All MGP assays described above have in common that – if
However, further research is necessary to establish the value of
this assay.
Ongoing research and future perspectives of MGP as
We aimed to develop an MGP ELISA to follow-up vitamin
K-status after intervention (e.g. supplementation with vitamin
K, or treatment with coumarin derivatives).Additionally, we in-
tended to measure MGP species which are most readily set free
in the circulation, independent of the presence of vascular cal-
ing the very negatively charged carboxylated or phosphorylated
domains have a high affinity for precipitated calcium and will
accumulate in and around calcified lesions in the vasculature
(Fig. 2).As we found that in patients prone for vascular disease/
calcification both the pMGP and ucMGP where decreased (see
above), we hypothesise that only the non-phosphorylated, non-
culation, independent of the vascular tissue calcium content,
since this conformation has the lowest affinity for calcium (Fig.
2).Therefore, we developed a sandwich ELISA measuring non-
phosphorylated, non-carboxylated MGP (dp-ucMGP).
We first tested the dp-ucMGP assay in a healthy control
and older. The dp-ucMGP fraction was indeed measurable in
plasma of these apparently healthy subjects (data not shown).
The presence of inactive MGP in healthy subjects is consistent
with data on osteocalcin, another vitamin K-dependent protein
that the vitamin K-status is sufficient for normal haemostasis,
but that extra-hepatic tissues such as bone and vascular are mar-
ginal in vitamin K (93, 112, 114). Secondly, we measured dp-
receiving vitamin K-antagonists (coumarin derivatives) as oral
anticoagulant therapy and healthy volunteers receiving supple-
ments with vitamin K (Fig. 3). Significantly increased circu-
K-antagonists,whereaslowlevelsofdp-ucMGP werepresent in
healthy volunteers on vitamin K-supplementation. When MGP
status was measured before and after a period of high vitamin K
intake it was found that the dp-ucMGP level even decreased
become a marker for vitamin K-status of the arterial vessel wall.
which will be published elsewhere.
Vascular calcification is a major determinant of cardiovascular
mortality and recent data demonstrate that one of the main cal-
cular calcification is associated with poor cardiovascular out-
massive calcification is not related to plaque stress (115). In-
spection of human atherosclerotic lesions revealed an associ-
ation between plaque rupture and punctated intimal calcium de-
position, possibly originated from small cell membrane frag-
ments (116). Thus, the exact role of calcification in unstable
plaque development is still unknown. The value of the calcifi-
cation score (assessed by multislice CT scan) is therefore still
under debate. Although calcification is regarded as an actively
regulated process, it is likely that the massive arterial calcifi-
cations represent an end-stage process. The measurement of
biomarkers, which can reflect the early signs of vascular disease
could be of great importance. Both cardiovascular calcification
and MGP activity are directly correlated with vitamin K2intake
(6, 47, 81). Remarkably, most subjects in the healthy population
are not optimally protected against calcification, since part of
their MGP occurs in an uncarboxylated, inactive form (93, 106).
be regarded as an independent risk factor for CVD; fortunately,
Experiments in rats suggest this possibility by regression of cal-
cification (47), but presently no data in humans are available to
suggest that high vitamin K intake may contribute to regression
of vascular calcification in CVD patients. Accumulating data
suggest, however, that a high vitamin K2intake may be an effec-
tive interventional strategy to decrease the calcification risk in
the general population.
Figure 3:The dp-ucMGP assay is based on the sandwich ELISA-
principle. In brief, monoclonal anti-dpMGP was coated to the micro-
titer plate.After blocking, either sample (citrated plasma or EDTA) or
standard was incubated.The standard peptide was synthetic MGP, based
on the non-phosphorylated 3–15aa sequence and the non-carboxylated
35–54aa sequence, linked with a hydrophilic spacer (Pepscan, Lelystad,
the Netherlands).After incubation and washing, the standard or sample
was detected using a biotinylated monoclonal ucMGP antibody. Plasma
dp-ucMGP levels in the reference subjects, patients on oral anticoagulant
treatment and subjects receiving vitamin K supplements are depicted.
The reference group was divided into two groups: age less than 40
years, and age 50 or more. Mean ± SD ucMGP values of young healthy
controls, elderly healthy controls, patients on coumarins and subjects re-
ceiving vitamin K-supplements were 389 ± 182, 312 ± 109, 172 ± 82,
and 140 ± 55 nM, respectively (depicted as horizontal bars).
Schurgers et al. Matrix Gla-protein and vascular calcification
New vitamin K-dependent proteins
Page 10
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5 bedroom terraced house to rent Cowley Mill Road, UxbridgeSTUDENTS! STUDENTS! STUDENTS! Lords Associates of London are pleased to offer this spacious 4 bedroom property, a 10 minute walk from Brunel University.Property consists of large bedrooms, a family bathroom, a fully fitted kitchen and a garden at the rear. More details ›
£1,200 pcm
2 bedroom apartment to rent Church Road, CowleyCameron Estate Agents are delighted to offer back to the market this newly built ground floor two bedroom apartment located in Cowley close to Brunel University and Hillingdon Hospital. The apartment benefits from parking and security entry. Fitted luxury kitchen open plan to the reception, famil... More details ›
£1,700 pcm
4 bedroom terraced house to rent Mill Avenue, UxbridgeFOUR BEDROOM STUDENT LET : Located a short distance from Brunel, is this four bed, one reception room student house. The property has three doubles and one single bedroom, with a large lounge/kitchen area. Rear garden and furnished. More details ›
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