As I first wrote about back in 2007 in my article, “On the Trail of the Elusive X Factor,” matrix Gla protein (MGP) is a vitamin K-dependent protein that directly protects soft tissues from calcification and (whether directly or indirectly) helps mineralize bones and teeth. MGP is mostly made by cartilage cells and vascular smooth muscle cells. Most of the MGP in the blood probably comes from the blood vessel wall. Investigators are currently measuring blood levels of MGP in research studies, and in the foreseeable future MGP may become available to health care practitioners and patients as a marker for blood vessel vitamin K status.
Making use of MGP in clinical or research settings is complicated by the fact that it exists in several different forms (1). Before MGP can function properly, the enzymatic machinery of our cells activates it in two steps: the addition of phosphate, known as phosphorylation, and the vitamin K-dependent addition of carbon dioxide, known as carboxylation. Each of these steps gives negative charges to MGP that help it bind to positively charged calcium. As a result, MGP may appear in the blood when in a fully activated form, a fully inactive form, or a partially activated form â€” either phosphorylated but not carboxylated, or caroboxylated but not phosphorylated. To date, the tools only exist to measure two of these in human blood with specificity: MGP that is fully inactive and MGP that is carboxylated but not phosphorylated. Additionally, we can measure the total pool of uncarboxylated MGP, regardless of whether it is phosphorylated.
At first thought, it would seem that since vitamin K is needed to carboxylate MGP, the total pool of uncarboxylated MGP should inversely reflect blood vessel vitamin K status. I’ll refer to to this as t-ucMGP. In other words, when our blood vessels have a rich supply of vitamin K, the pool of t-ucMGP should fall, and vice versa. That, however, is not the case (1). The current data seem to indicate that some 99.9% of this pool is phosphorylated, and it turns out that just being phosphorylated allows MGP to stick to calcium deposited in the blood vessel wall. Thus, if the blood vessel has poor vitamin K status, it will produce more uncarboxylated MGP, which should cause the blood level of t-ucMGP to rise. This poor vitamin K status, however, will also cause the blood vessel to begin calcifying, which will cause MGP that is phosphorylated but not carboxylated to stick to the calcium, causing the blood level of t-ucMGP to fall. Thus t-ucMGP could rise, fall, or stay the same in response to poor vitamin K status, making it an unreliable marker.
On the other hand, even though MGP that is fully inactive, neither phosphorylated nor carboxylated, represents only a tiny proportion of the uncarboxylated MGP found in human blood, since it can’t stick to vascular calcifications, it may be a good marker of vitamin K status. The technical name for this form of MGP is desphospho-uncarboxylated MGP. I’ll refer to this form as dp-ucMGP.
In support of this idea, 180 and 360 micrograms per day of vitamin K2 as MK-7 supplemented for twelve weeks decreased dp-ucMGP in healthy subjects, but had no effect on other forms of MGP (2).
Two other studies have shown that dc-ucMGP responds to vitamin K supplementation. MK-7 dose-dependently decreased dp-ucMGP in hemodialysis patients at doses of 45, 135, and 360 micrograms per day supplemented for six weeks (3). Similarly, three years supplementation with 500 micrograms per day of vitamin K1 decreased dp-ucMGP (4).
Immunodiagnostic Systems (IDS) will begin offering the test for dp-ucMGP later this year. A representative from IDS told me that they would begin offering it for research use, but pending FDA approval they hope to make it available for clinical use as well.
Another company to keep your eye on is VitaK, which hopes to produce tests for vitamin K status that can be used “for home diagnostics, thus allowing interested consumers to find out his/her vitamin K status, and to monitor improvement thereof while taking supplements or functional foods.”
These advances will help democratize vitamin K research and diversify the types of foods that can be studied. There are a lot of gaps in our knowledge of the vitamin K2 contents of various foods grown and raised under various conditions, but what we really want to know is how well those foods support the biological activities we attribute to vitamin K, which is something we will be able to measure once these tests are available.
1. Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft-tissue calcification. Adv Nutr. 2012;3(2):166-73.
2. Dalmeijer GW, van der Schouw YT, Magdeleyns E, Ahmed N, Vermeer C, Beulens JW. The effect of menaquinone-7 supplementation on circulating species of matrix Gla protein. Atherosclerosis. 2012;225(2):397-402.
3. Westenfeld R, Krueger T, Schlieper G, Cranenburg EC, Magdeleyns EJ, Heidenreich S, Holzmann S, Vermeer C, Jahnen-Dechent W, Ketteler M, Floege J, Schurgers LJ. Am J Kidney Dis. 2012;59(2):186-95.
4. Shea MK, O’Donnell CJ, Vermeer C, Magdeleyns EJ, Crosier MD, Gundberg CM, Ordovas JM, Kritchevsky SB, Booth SL. Circulating uncarboxylated matrix gla protein is associated with vitamin K nutritional status, but not coronary artery calcium, in older adults. J Nutr. 2011;141(8):1529-34.