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 — 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.
Read more about the author, Chris Masterjohn, PhD, here.
References
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.
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i had a blood nutrient test done by spectracell and the test indicated that i was low on vitamin k2. have they already found a way to test vit k2 since you’re reporting that studies are looking for ways to test vit k.
Hi Melv,
I’m not sure what they tested, if it was just K2, then that tells you how much K2 was in your blood. This test would tell you whether your blood vessels are getting enough K2 to activate the proteins they need. It’s a functional marker.
Chris
Hi Chris,
I am an Italian medical doctor. Did you see my email about a workshop here in Italy?
Andrea L.
I’ve been Vitamin K2-ing for years now but not one physician, GP or specialist, has ever heard of this vitamin. Of course I provide them with their own ‘home CE course’ directive but the big question is: when do we achieve the tipping point?
Here in Ontario, the government health insurance stopped coverage for Vitamin D blood testing a couple of years ago. Recently I paid $50 to have mine checked and it was reassuring to discover that the supplement I take has definitely done the job. But to even consider in my wildest imagination that any testing for vitamin K2 status would ever, in my lifetime, become routine, beggars belief.
Around here the osteoporosis drugs are king and queen. In Europe an alternative to Coumadin is available. Not here. The treating physicians appear to lack the knowledge that Coumadin increases the rate of development of atherosclerotic plaque.
Legally, only 1000 IU Vitamin D3 doses are available. K2 is only available in maximum 120 microgram doses. Acquiring higher dosages of Vitamin D3 requires cross bordering smuggling.
Seems like a dose in excess of around 45mcg (mk-7)per day is approaching a pharmacological effect rather than addressing a deficiency. I’m not convinced that full carboxylation of osteocalcin or mgp is necessary or desirable. Personally, I feel terrible if I take more than about 45mcg every few days.
It happened a few times where I thought I was getting sick only to later make the connection that it was during a period of higher k-2 supplementation. This was in the context of sufficient A and D levels. I remember seeing a study where daily natto eaters had far less heart disease as their non-natto-eating counterparts, but twice the rate of diabetes. Being prone to hypoglycemia, this may be why I react in this way.
Anyway, I think these dosages may be excessive for certain susceptible individuals, and probably unnecessarily high for the rest. We need to work backward from what amount supports strong bones and teeth and prevents calcification of soft tissue rather than what maximally carboxylates these molecules.
Hi Travis,
I doubt it’s desirable or even possible to fully carboxylate osteocalcin because bone resorption causes the decarboxylation and release of osteocalcin into the plasma, and bone resorption is always happening to some degree, but I’m not so sure anything similar is true of MGP. Regardless, I agree that we need to look at clinical effects as the ultimate criterion of sufficiency and deficiency, but having markers like this is incredibly useful as long as they don’t supplant that goal because studying the clinical effects is far more difficult, takes far more time, and can’t be done for each person. I don’t think >45 mcg/day is approaching a pharmacological dose — it definitely isn’t, because it’s easy to obtain this from food. Whatever the explanation for your experience, it is not that. What brand do you take? Have you tried another one, or tried MK-4?
Chris
Seems like greater than 45mcg a day of long-chain menaquinones doesn’t really occur without dairy and that much mk-7 doesn’t occur without natto. Maybe the problem is mk-7 itself, because I don’t get it from eating a lot of cheese (which I think is mostly mk-8/9). Although, now that I think of it, I’ve gotten this effect with large doses of MK-4 as well.
We exchanged a few e-mails a while back when I asked for your opinion about an arrhythmia that arose when my 25(OH)D levels happened to be fairly high (in the 90s) and that actually turned out to be the result of K2 as well.
I’ve tried 5 different k2 supplements, all with the same effect. I think a diet with as many egg yolks, and with as much cheese and dark chicken meat as I eat must be sufficient and the supplements are pushing me over the edge.
Anyway, thanks a lot for all of the great work you do.
Hi Travis,
It’s on the high end of what is possible, but it’s easily possible with a diet. You could get it without consuming dairy if you consumed a lot of, say, egg yolk, or even a little goose liver. I can’t think of what the K2 could be doing other than you may have a high conversion of it to menadione, which is vitamin K without a side chain, and is toxic. I can’t remember how it is metabolized, but I think it is glutathionylated, so it could deplete glutathione for example. Thank you very much for sharing your experience.
Chris
@Travis: I wonder if the bad feeling after the k2 is form magnesium deficiency. Vit d uses mg, possibly adding the k2 increased mg needs. Low mg will make you feel awful. I’ve seen people have this happen when they take a higher vit d dose
I’m always seeing K2 discussed in mcg amounts, yet the Thorne drops are 1 mg/drop.
I’ve always been uncomfortable about the order of magnitude difference, or am I confused that 1mg/drop is not 1000 mcg/drop?
I have my children taking 2 drops/week, and I take the same amount as well. It makes an incredible difference in how clean my teeth feel, but that’s about all I’ve noticed with it personally. Anyone care to comment? Should I, or perhaps more appropriately, would you be cutting this about a 50 or 100 times? (heh, insert homeopathy joke)
BTW, what caused me to get serious about taking K2 was my son having a terrible trip to the dentist last year. The dentist said he had 6 cavities. After 9 months of K2 we went back and he was down to 2. I’m always suspicious of dentists, but what can you do?
Regards.
Kind of surprised that no one on this site has reviewed or made mention of the wonderful book on the topic by Dr. Kate Rheaume_Bleue, entitled Vitamin K2 and the Calcium Paradox. It is a wealth of good information.There is also an interview of her on Mercola
I will eventually. Thanks Eliot.
Chris
High dose Vitamin K2 makes me feel like I’m having a panic attack; even low doses of around 45 micrograms seems to flatten out my emotions and gives me an over all weird feeling.
The positive effect Vitamin K has on bones is apparently the result of vitamin K’s agonism of the SXR receptor; activating this receptor, however, results in the induction of CYP3A4, resulting in increased deactivation of testosterone.
Further, K2, in relatively high doses, induces cyp11a, which should result in increased synthesis of testosterone; but, since it is involved in the first step of the synthesis of all steroid hormones, it also will increase many other steroid hormones, including the glucocorticoids and mineralcorticoids, depending on the relative saturation of the enzymes responsible. This effect is likely to be seen only with the relatively high doses.
Vitamin K2 is no panacea.
I think our understanding of vitamin K2 as a signaling molecule is in its infancy and we have little idea how complex it is right now, and this could account for adverse reactions to it. However, it’s effect on bone is clearly linked at least in part to its role in carboxylating osteocalcin and MGP.
Chris
Hi Chris,
I am a fit and healthy Australian 69 year old male with all my January 2018 extensive blood tests coming back within recommended ranges. Not overweight, do not have diabetes, etc, good fasting insulin result, regularly fast for 24 hour periods and often in ketosis.
To my surprise, my first ever CT coronary calcium score in January 2018 returned a value of 1507. Subsequent Exercise Myocardial perfusion test states good exercise capacity for age, no definite scan evidence of an exercise induced reversible perfusion defect to suggest inducible myocardial iscaemia and no chest pain in response to satisfactory cardiac workload for age.
I immediately started taking daily 360µg Vitamin K2 menaquinone-7 (MK-7) each morning and again 360µg Vitamin K2 menaquinone-7 (MK-7) each evening.
I hope this will either maintain my calcium score at its current value, but hopefully reverse the trend.
Is it possible to test my current level of activated MGP (dp-ucMGP)?
I will undertake another calcium score in 2019. Would another test of my (dp-ucMGP) be a good indicator also of the hopefully positive effect of K2.
Do you believe taking K2 at this level for the rest of my life be negative and do you think anything else is needed to activate the K2 to reduce my high calcium score?
Regards,
Bryan Horton
Hi Chris,
I am 66 year male with moderate Aortic Stenosis with a history of Rheumatic Fever at age 14 but, no symptoms. I started taking Vitamin K2 almost 3 years ago and gradually increased my dosage in October 2018 to 360 mcg daily and 5000 iu of Vitamin D3. I also eat 1 organic cage free egg per day and 1 white container of Japanese made Natto.
Otherwise I eat a Mediterranean diet with loads of greens, complex carbs, nuts and salmon. No processed foods and junk or soda . I walk at least 5 miles per day and also do weightlifting. I wanted to seek your thoughts on my health situation?
I saw 1 of You Tube Vitamin K2 videos yesterday and really enjoyed it.
Thank you
Tom Salem
978-551-3076