Most of us know vitamin K2 as that vitamin you should take with vitamin D. And the reason for that is that vitamin D increases the body's production of proteins that depend on vitamin K2 to activate them, referred to as "K2-dependent proteins". 

The K2-dependent proteins most people are familiar with are osteocalcin and matrix gla protein because these proteins regulate calcium metabolism when they are activated by K2 in carboxylation reactions that carboxylate (add carbon dioxide to) the uncarboxylated versions of these proteins. 

Carboxylated osteocalcin is involved with bone formation and mineralization. Carboxylated matrix gla protein prevents calcification of soft tissues. In other words, carboxylated osteocalcin puts calcium in bones, and carboxylated matrix gla protein keeps calcium from calcifying soft tissues, especially blood vessels, and plays a role in bone organization. 

In case you wonder what the "gla" in "matrix gla protein" means, "gla" is an abbreviation for the gamma-carboxyglutamic domain of proteins that have such domains, like matrix gla protein does. 

Under-carboxylation of these K2-dependent proteins leads to soft tissue calcification, reduced bone density, varicose veins, wrinkles, heart disease, and more. Evidence is growing that vitamin K2 deficiency a significant dietary factor in heart disease.

You probably already know all or most of that. But the K2 story has many more chapters that are even more interesting. Vitamin K2 is involved in mitochondrial function and therefore affects every aspect of metabolism. It also activates another K2-dependent protein called growth arrest-specific 6 (GAS6) with far-reaching implications. (1)

Vitamin K2 in Mitochondrial Function

You might know that coenzyme Q10 has a key role in the electron transport chain of transferring electrons from Complex I and II to Complex III. Vitamin K2 transfers electrons from Complex I to Complex III, but not from Complex II to Complex III. This is probably why the presence of vitamin K2 increases energy production via the electron transport chain. (2) A deficiency of coenzyme Q10 could place extra demand on your vitamin K2 status by causing the electron transport chain to lean more heavily on vitamin K2 to support the transfer of electrons from Complex I to Complex III.

In the image below, vitamin K2 is represented as "VitK2" in a green oval,and coenzyme Q10 is represented as "Q" in pink circle.

Since mitochondrial dysfunction plays a central role in diabetes, cardiovascular disease, nerve cell dysfunction, cancer, and accelerated aging, it is not surprising that science is discovering numerous connections between vitamin K2 status and these disorders. But it's role in mitochondria is not necessarily the most important mechanism by which is has its wide-ranging influences on health. 

Diabetes

The main mechanisms driving type 2 diabetes are mitochondrial dysfunction (usually caused by toxins or oxidative stress), nutrient deficiencies, inflammation, oxidative stress, membrane dysfunction, and membrane receptor dysfunction. 

Vitamin K2 deficiency plays a role in all of these mechanism, and vitamin K2 consumption has been found to be inversely associated with the risk of diabetes. (3) In other words, people with the lowest consumption of vitamin K2 had the highest risk of diabetes, and people with the highest consumption of vitamin K2 had the lowest risk of diabetes. Every 10 mcg increment of vitamin K2 intake reduced the risk of diabetes by 7%.

Vitamin K2 in the MK-7 form has been shown to reduce the progression of insulin resistance and improves insulin sensitivity by activating osteocalcin (4), that K2-dependent protein that is more well-known for it's role in calcium metabolism. It turns out that osteocalcin has multiple endocrine functions.

Neuropathy

One of the complications of diabetes is peripheral neuropathy. Neuropathy is also often associated with deficiency of vitamin B12 or other B vitamins. In a study comparing the administration of vitamin B12 to the administration of vitamin K2 to patients with peripheral neuropathy either due to B12 deficiency or diabetes, the group of diabetic patients that received vitamin K2 had a similar or greater reduction in symptoms of neuropathy than the B12-deficient group that received vitamin B12. (5)

Neuropathy in people with type 2 diabetes is associated with uncarboyxlated (unactivated) matrix gla protein (6), so it makes sense that administering vitamin K2 would help with symptoms of polyneuropathy in patients with type 2 diabetes.

Vitamin K2's reduction in the symptoms of peripheral neuropathy could also be do, at least in part, to its potential to improve mitochondrial function. And vitamin K2 also has potent antiinflammatory properties that probably contributed to the reduction in neuroopathy symptoms.

A K2-dependent protein called growth arrest-specific 6 (GAS6) activates a type of receptor called a TAM receptor, which then inhibits the activation of proinflammatory nuclear factor kappa beta (NF-kB). NF-kB activation increases inflammatory cytockines like interleukin-6 (IL-6), interleukin 1-beta (IL-1B), and TNF-alpha (TNF). (7) So vitamin K2's inhibition of NF-kB reduces the elevated expression of IL-6, IL-1B, and TNF that mediate inflammation in peripheral neutopathy.

Parkinson's Disease

In a study comparing 93 Parkinson's disease patients with 95 healthy controls, the Parkinson's patients had significantly lower levels of vitamin K2. (8) And the progression of Parkinson's disease was associated with progressively lower vitamin K2. The authors hypothesized that lower vitamin K2 could contribute to Parkinson's disease by reducing vitamin K2's availability to regulate inflammatory responses and other processes involved in Parkinson's disease.

In research using mouse dopamine neurons (a mouse model for Parkinson's disease), cells were subjected to 6-hydroxydopamine (6-OHDA), followed by a treatment with vitamin K2. The 6-OHDA caused mitochondrial dysfunction, and the vitamin K2 substantially protected against and reversed the mitochondrial dysfunction in the 6-OHDA-damaged dopamine neurons. (9)

More specifically, 6-OHDA increased reactive oxygen species (ROS) and membrane depolarization and promoted apoptosis (cell death) and abnormal mitochondrial fission and fusion.

Vitamin K2 significantly reduced OHDA-induced changes by reducing reactive oxygen species (ROS), membrane depolarization, and apoptosis, while restoring more normal balance between mitochondrial fission and fusion.  Vitamin K 2 also promoted mitophagy and induced mitochondrial biogenesis.

These results could hold promise for vitamin K2 in the treatment of Parkinson's disease.

Alzheimer's Disease

A review article (10) highlighted growing evidence for a link between vitamin K2 status and Alzheimer's disease and interestingly made the case that vitamin K2 synthesized by bacteria in a healthy small intestine microbiome can be absorbed in the ileum. Normally, it is assumed that vitamin K2 is only synthesized by bacteria in the colon and is not absorbed there.

Vitamin K2 in the MK-4 form has been shown to reduce amyloid beta aggregation and cytotoxicity in Alzheimer's disease. (11) MK-4 is the form of vitamin K2 that is most prevalent in the brain. 

Cardiovascular Health

A study of aerobically trained men and women looked at the effect of 8 weeks of supplementation with vitamin K2 on cardiac output and found that K2 supplementation increased cardiac output. (12) The participants received 300 mg daily of vitamin K2 (MK-7 form) for weeks 1 to 4, and then 150 mg daily for weeks 5 to 8, while they maintained their physical exercise habits during the 8-week period. The group that received the K2 supplements experienced a 12% increase in cardiac output compared to the placebo group. 

WIthout hthis supplementation with vitamin K2, this degree of change in cardiac output in an already-fit population would be expected to take 6 months, according to the study authors. They concluded that K2 supplementation (MK7 form) appeared to reduce the training window for achieving these effects by about 60%.

These results could probably be extrapolated to mean that supplementation with vitamin K2 would also help less athletic people also experience better cardiac output and overall cardiac health.

A study of healthy postmenopausal women given vitamin 180 mcg of K2 (MK-7 form) for 3 years, the group receiving the vitamin K2 showed reduced arterial stiffness, especially among the women with high age-associated arterial stiffness. (13)

Cancer

A review of studies that included both in vitro (in glass, "test tube") and in vivo (in living organisms) studies, vitamin K2 was seen to inhibit the growth of cancer cells via numerouse mechanisms. (14) 

In a study of women with liver cirrhosis, the group of women given 45 g per day of vitamin K2 had an 87% lower incidence of hepatocarcinoma (liver cancer) compared to the group that was not given vitamin K2. (15)

In a mouse model of prostate cancer, vitamin K2 reduced NF-kB signaling and cell proliferation, induced apoptosis, and reduced angiogenesis, the ability of prostate cancer cells to stimulate the production of new blood vessels to support their metabilism. This was accomplished in part via the PI3K-Akt (AKT) signaling pathway, which promotes survival and growth in response to extracellular signals. (16) Dysfunctional PI3K-Akt pathway regulation can lead to an increase in signaling activity that keeps cancer cells alive and has also been linked to type 2 diabetes and many other diseases.

In the image below from the study, "VK2" represents vitamin K2. and shows its inhibition of NF-kB and AKT and its promotion of the Caspase signaling pathway that can lead to  cancer cell death via mitochondrially-mediated apoptosis, which is normally not working properly in cancer cells.

Vitamin K2 was also shown to induce apoptosis in human ovarian cancer cells. (17)

Muscle Cramps

In a  small study of 19 people with muscle cramps of unknown cause, 100 mcg of daily vitamin K2 (MK-7) virtually eliminated muscle cramps in 3 months. (18) The 19 participants were divided into two groups with differing degrees of muscle cramp frequency and severity. Here is how the study described the results:

"Patients from the Group A (n=9) had 1-2 cramps/day to 5 /day with severity of 2-9 of VAS (visual analog score) and duration of 1 min to 10 min. Patients from the Group B (n=10) had lesser frequency of 2-4/wk to at least once a week. Duration of cramps varied from less than 1 min 10 min with severity of 2-8 of VAS. Patients from both the groups experienced a reduction in the frequency except one from the Group B. In the Group A, muscle cramps reduced from 1-2 cramps/day (n=8) to 5 /day (n=1) at base line to 0 cramps (n=8) to 2-3/ month (n=1) during therapy. In patients from the Group B, cramps 2-4/wk at baseline were reduced to 0 - 1/month during the therapy."

In other wrods, the incidence of cramps was dramatically reduced for all but one study participant. The implications of the study are limited by the small study group and lack of control group, but the results are quite promising. 

Testosterone (and Estrogen)

In rats fed 75 mg of vitamin K2 (MK-4) per kg of rat chow for 5 weeks, testosterone levels were significantly elevated from week 2 and reached the highest level in the 5th week. (19) As you can see in the image below from the study, at week 5 testosterone in rats fed the K2-supplemented chow was almost 90% higher than that in rats not supplemented with K2.

Without knowing how much rat chow a rat eats per unit of its body weight, it is hard to estimate what the equivalent human dose of vitamin K2 would be. But it is probably fair to say that the average rat weighs much less than 1 kilogram and probably more like one half kilogram. So 1 kg of food would equate to about twice the rat's body weight. 

How long does it take a rat to eat twice it's weight in food? Who knows, but my guess would be about 6 months. If that were the case, then the rat would be eating 75,000 mcg vitamin K2 / 180 days = 416.7 mcg per day of vitamin K2.  If the rat weighs one half kg, then the amount of vitamin K2 per kg that the rats were eating was 416.7 x 2 = 833 mcg per kg of body weight. In a 60-kg human, this would equate to 50,000 mcg, which is similar to the amount of vitamin K that has been used in various Japanese experiments in humans that used 45,000 mcg daily.

In another study, rats fed a diet deficient in vitamin K2 (MK-4) exhibited lower testosterone in plasma and in the testes than rats fed a diet sufficient in K2. (20) Expression of the gene that synthesizes testosterone, CYP11A, was reduced in the K2-deficient group, suggesting that vitamin K2 regulates expression of CYP11A. 

When treated with lipopolysaccharide (LPS), a highly inflammatory component of the outer cell membranes of pathogenic bacteria, rats fed the diet deficient in vitamin K2 experienced a greater decrease in testosterone than the rats not fed the K2-deficient diet. (21) The study authors hypothesized that vitamin K2 reduces the inflammatory response to LPS. LPS enters the body when the gastrointestinal tract has more gram-negative bacteria (dybiosis) and is hyperpermeable ("leaky"). 

By the way, since metabolic syndrome and diabetes is strongly associated with "metabolic endotoxemia" (the excessive translocation of bacterial endotoxins such as LPS to the bloodstream), a deficiency of vitamin K2's protective effect against LPS-induced inflammation could be another mechanism by which vitamin K2 deficiency contributes to metabolic syndrome and diabetes.

Since estrogen is produced from testosterone via the enzyme called aromatase, any effect of vitamin K2 on testosterone production would probably ultimately also apply to estrogen. But the relationship of vitamin K2 to estrogen appears to be even more interesting than that.

Vitamin K2 was shown to reduce the intracellular (inside of cells) ratio of estradiol to estrone (22), which could mean that vitamin K2 might protect against excessive estrogenic signaling. In fact, I have heard that many women with estrogen dominance that interferes with normal thyroid function have benefitted from taking vitamin K2 to modulate estrogen metabolism and thereby improve their thyroid function. But I would not expect vitamin K2 to reduce estrogenic signaling when estrogenic signaling is abnormally low. 

In fact, we can probably expect to see evidence emerging in the research on vitamin K2 that it has hormone-like effects that depend on the overall biochemical context. Because of the effects that vitamin K2 elicits in the body and the manner in which it does so, researchers are already starting to view vitamin K2 as a hormone. (23) 

Which Form of Vitamin K2 Should I Use?

MK7 is the form of vitamin K2 produced by bacterial metabolism and is found in the fermented soy product called natto that is consumed in Japan. MK-7 can be produced by certain gut bacteria, but human gut microbiomes (or at least in modern humans) does not seem to produce enough MK-7 for optimal health, or produces it in a location from which it  cannot be absorbed (the colon).  

MK-4 is the form of vitamin K2 found in animal-based foods like dairy (especially certain cheeses), certain types of seafood, egg yolks, certain meats (e.g. chicken legs),, emu oil, and organ meats. MK-4 is also the form of vitamin K2 that is most prevalent in the brain. 

MK-7 has a longer half-life in the body than MK-4 and seems to be the form that has been used in most studies. But MK-4 was used in a Japanese study to reverse arterial calcification. In those studies, very high doses of 45,000 mcg (15,000 mcg three times per day) of MK-4 was used. A study using just 90 mcg of MK-7 and 10 mcg of vitamin D3 showed a small decrease in the progression of arterial calcification but no reversal of calcification. (24) With such widely divergent dosing and results using MK-7 and MK-4, clearly there need more studies comparing similar doses of MK-7 and MK-4.  

I would suggest using both MK-4 and MK-7 rather than only one or the other. If forced to choose, perhaps the decision should depend on what medical condition one is trying to address and which form of vitamin K2 was used and demonstrated benefits in research.

How Much Vitamin K2 Do I Need?

The human studies mentioned in this post employed dosages between 150 and 300 mcg of MK-7 daily, and up to 45,000 mcg of MK4 to achieve the benefits observed in those studies.

It also seems possible that a healthy human microbiome could produce all of the MK-7 it needs. The review article on Alzheimer's mentioned previously focused made the case that vitamin K2 synthesized by bacteria in the small intestine is absorbed in the ileum before arriving in the large intestine where it is unlikely to be absorbed. But this would not contribute to MK-4 levels in the brain or anywhere else in the body, unless we discover that humans can convert other forms of vitamin K2 to MK-4.

Microbiome bacteria that are known to produce vitamin K2 (MK-7 and other forms other than MK-4) include the following species:

• Bacillus subtilis
• Lactic acid bacteria
• Bifidobacteria species
• E. coli
• Eubacterium lentum
• Veillonella species
• Enterobacterium species
• Bacteroides species

Probiotic supplements contain the first three types listed above.

A Bright Future For Vitamin K2

It seems that science is only beginning to unravel the diversity of roles vitamin K2 plays in the body and that there is a bright future for research on vitamin K2 and its use in treating many diseases. In the meantime, be sure that your vitamin K2 intake is adequate, especially if you take high doses of vitamin D because that increases your need for vitamin K2. 

References:

1. Review article on K2's far-reaching activities: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9237441/

2. Mitochondrial function
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184094/

3. K2 consumption associated with reduced risk of type 2 diabetes
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909045/

4. K2 improves insulin sensitivity via osteocalcin metabolism
https://diabetesjournals.org/care/article/34/9/e147/38664/Vitamin-K2-Supplementation-Improves-Insulin 

5. K2 reduced symptoms of diabetic peripheral neuropathy: https://www.researchgate.net/publication/330787720_A_novel_potential_role_of_Vitamin_K2-7_in_relieving_peripheral_neuropathy

6. Uncarboxylated matrix gla protein associated with diabetic polyneuropathy: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039520/

7. K2 depentden protein GAS6 regulates NF-kB and more
https://ashpublications.org/blood/article/123/16/2460/32646/TAM-receptors-Gas6-and-protein-S-roles-in

8. Lower K2 levels in Parkinson's disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485738/

9. Parkinson's disease in a mouse model of K2's protection against damage to dopamine neurons
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9003256/

10. Review article on the increasing evidence linking K2 status with Alzheimer's disease and making a case that microbiome-generated vitamin K2 can be absorbed in the ileum
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308377/

11. K2 reduces amyloid beta aggregation and cytotoxicity in Alzheimer's disease
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000266/

12. K2 supplementation increased cardiac output: https://pubmed.ncbi.nlm.nih.gov/28646812/

13. K2 supplementation reduced arterial stiffness: https://pubmed.ncbi.nlm.nih.gov/25694037/

14. Review article about vitamin K2's inhibition of the growth of cancer cells
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958717/

15. Vitamin K2 reduced hepatocarcinoma by 87% in women with liver cirrhosis
https://jamanetwork.com/journals/jama/fullarticle/199121

16. K2 promotes apoptosis and inhibits NF-kB and angiogenesis in mouse prostate cancer
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3767046/

17. K2 promotes apotosis in human ovarian cancer cells
https://pubmed.ncbi.nlm.nih.gov/18202854/

18. Vitamin K2 reduced muscle cramps
https://www.researchgate.net/publication/283665694_Therapeutic_Activity_and_Safety_of_Vitamin_K_2-7_in_Muscle_Cramps_An_Interventional_Case-Series

19. Vitamin K2 increased testosterone in rats
https://lipidworld.biomedcentral.com/articles/10.1186/1476-511X-10-158

20. Vitamin K2 deficiency lowers testosterone and CYP11A gene expression in rats
https://www.sciencedirect.com/science/article/abs/pii/S0304416506001590

21. Vitamin K2 ameliorated the reduction in testosterone in rats exposed to LPS
https://pubmed.ncbi.nlm.nih.gov/21894328/

22. Vitamin K2 appears to decrease the ratio of estradiol to estrone
https://pubmed.ncbi.nlm.nih.gov/15763078/

23. Vitamin K2 starting to be considered a hormone
https://www.intechopen.com/chapters/65878

24 MK-7 showed minor decrease in calcification: https://pubmed.ncbi.nlm.nih.gov/26176325/