A brief history of vitamin K
Way back in 1929, when researchers first discovered vitamin K (VK), they focused mainly on the vital role of this fat-soluble vitamin in the blood-clotting process (coagulation). To this day, it’s still known as the “clotting vitamin”, even though research shows it plays many other important roles.
At the time, researchers identified three basic forms of VK – vitamin K1 (phylloquinone), vitamin K2 (menaquinone or MK) and vitamin K3 (menadione), a potent synthetic form of vitamin K not used in humans.
They initially considered these to be straightforward structural variations of VK. Several years later, however, they discovered that each form of VK also has subtype compounds.
For example, vitamin K2 has the subtypes MK4 (found in animal products like meat and dairy) and MK7, a natural product of the bacteria that live in the lower intestine.
In detail – Vitamin K2 is produced by our intestinal bacteria, and a healthy microbiome will produce enough to support both bone and heart health. People with bacterial overgrowth, however, have altered vitamin K2 metabolism.
That is, the body’s microbiome can’t produce what’s needed to maintain health if the gut is experiencing bacterial overgrowth.
Absorbed in small quantities, vitamin K commences the cycle of absorption in the small intestine and it is delivered to the liver and other tissues via the lymphatic system.
The major portion of vitamin K1 is stored in the liver and the rest will join the vitamin K2 to be transferred by the low density lipoproteins to other tissues.
In human body, MK-4 to MK-10 vitamins are absorbed in greater amounts and show a higher biological activity than K1.
Mainly stored in the liver, vitamin K is found in small quantities in body.
Liver stores vitamin K1 and long-chain forms of vitamin K2.
Brain as well as glands such as pancreas and genital organs are among the other sites storing MK-4 .
Therefore, vitamin K deficiency does not equally affect all tissues.
For instance, liver, the main reservoir of vitamin K is the last organ to be affected in case of insufficiency or deficiency .
There is a body of evidence linking the shortage of vitamin K with increased risk of cancer, cardiovascular disease, soft tissue calcification, and osteoporosis.
Vitamin K Cycle
As described below, vitamin K is recycled through a cycle referred to as the vitamin K cycle. This enables the body to recycle and reuse vitamin k as many times as required to obviate the need for dietaries .
The cycle operates as follows.
Vitamin K enters the cells and functions as the cofactor of the endoplasmic reticulum resident -glutamyl carboxylase (GGCX), which carboxylates any selected glutamate residues on the target proteins and enables these proteins to bind to calcium .
Subsequently, vitamin K reductase enzyme converts dietary vitamin K to its reduced form (hydroquinone) which allows GGCX to load a –COOH group on specific proteins.
After carboxylation, vitamin K epoxide reductase converts back the resultant oxidized form of vitamin k to hydroquinone (Figure 1).
MK-7 rivals bone drugs — without the toxicity
First, let’s talk about MK-7 for bone.
A study last year (Zhu et al, 2017) found that MK-7 stimulates bone tissue and osteoblast precursors; so clear-cut are the effects that one Canadian researcher (Schwalfenburg 2017) noted that vitamin K2 “may be a useful adjunct for the treatment of osteoporosis, along with vitamin D and calcium, rivaling bisphosphonate therapy without toxicity.”
Notwithstanding my own perspective on whether bisphosphonate therapy is effective, this is a pretty extraordinary statement for a medical researcher to make!
MK-7 for healthy hearts and arteries
The benefits of MK-7 for reducing arterial hardening and cardiovascular disease are being explored by researchers at the same time.
The results so far have been extremely encouraging.
As a recent three year clinical trial using 180 mcg of MK-7 reported, “long-term use of MK-7 supplements improves arterial stiffness in healthy postmenopausal women, especially in women having a high arterial stiffness” (Knapen et al., 2015).
More recently, a 2017 study in kidney transplant patients — who commonly suffer from vitamin K2 deficiency — found that 8 weeks of MK-7 supplementation reduced arterial stiffness (Mansour et al. 2017).
As the Zhu study of MK-7’s effects on bones noted, MK-7 assists calcium in becoming mobilized out of the blood vessels and into the bone. Less calcium build up in blood vessels can mean less arterial stiffness. Vitamin K, it turns out, is crucial to as many as 17 different proteins that maintain bone and cardiovascular health (Wen et al., 2018).
How Do Vitamins K1 and K2 Work?
Vitamin K activates proteins that play a role in blood clotting, calcium metabolism and heart health.
One of its most important functions is to regulate calcium deposition.
In other words, it promotes the calcification of bones and prevents the calcification of blood vessels and kidneys .
Some scientists have suggested that the roles of vitamins K1 and K2 are quite different, and many feel that they should be classified as separate nutrients altogether.
This idea is supported by an animal study showing that vitamin K2 (MK-4) reduced blood vessel calcification whereas vitamin K1 did not .
Controlled studies in people also observe that vitamin K2 supplements generally improve bone and heart health, while vitamin K1 has no significant benefits .
However, more human studies are needed before the functional differences between vitamins K1 and K2 can be fully understood.
May Help Prevent Heart Disease
Calcium build-up in the arteries around your heart is a huge risk factor for heart disease .
Therefore, anything that can reduce this calcium accumulation may help prevent heart disease.
Vitamin K is believed to help by preventing calcium from being deposited in your arteries .
In one study spanning 7–10 years, people with the highest intake of vitamin K2 were 52% less likely to develop artery calcification and had a 57% lower risk of dying from heart disease .
Another study in 16,057 women found that participants with the highest intake of vitamin K2 had a much lower risk of heart disease — for every 10 mcg of K2 they consumed per day, heart disease risk was reduced by 9% .
On the other hand, vitamin K1 had no influence in either of those studies.
However, keep in mind that the above studies are observational studies, which cannot prove cause and effect.
The few controlled studies that have been conducted used vitamin K1, which seems to be ineffective .
Long-term controlled trials on vitamin K2 and heart disease are needed.
Still, there is a highly plausible biological mechanism for its effectiveness and strong positive correlations with heart health in observational studies.
Effects of Vitamin K on Osteoblast Function
Vitamin K affects the proliferation and differentiation of osteoblasts. It prevents the induction of apoptosis in osteoblasts and inhibits Fass-mediated apoptosis in a dose-dependent manner , but more effectively improves the osteoblast function.
As suggested in the literature, vitamin K2 treatment of osteoblasts could increase both the alkaline phosphatase activity and the level of bone anabolic markers such as OC in the cell medium.
The more the alkaline phosphatase activity is, the more the formation of the organic matrix and mineral part of the bone is, and so is the deposition of OC and hydroxyapatite in the bone.
Essential role of vitamin K in osteoblastic function through carboxylation pathway is well established. However, vitamin K2 performs some of its osteoprotective functions by upregulating bone marker genes.
Vitamin K2 activates the steroid and xenobiotic receptor (SXR) and operates as a transcriptional regulator of the number of osteoblastic biomarker genes and extracellular matrix related genes.
The SXR, also known as the pregnane X receptor (PXR), is a nuclear receptor which modulates gene transcription and its protective role in bone metabolism has been shown in PXR-knockout mice study . Research has the fact that vitamin K2 can induce upregulation of CYP3A4 (target gene of SXR) and activation of MSX2 (target gene for PXR).
Menaquinone-7 upregulates Tenascin C and bone morphogenetic protein-2 (BMP-2) genes expression .
The effects of vitamin K are not still limited to these pathways. Ichikawa et al. (2007) observed that MK-4, through a pathway independent of SXR and carboxylation, resulted in activation of two genes, namely, growth differentiation factor 15 and Stanniocalcin.
Induction of these genes is exclusive to MK-4, and vitamin K1 and MK-7 do not have such effects. The authors suggested that MK-4 regulates the expression of its target gene through a mechanism dependent on phosphorylation of protein kinase A.
Moreover, vitamin K2 supports bone formation and suppresses bone resorption by stimulating the expression of cytokines such as osteoprotegerin (OPG) and inhibiting the expression of receptor activator of nuclear factor kappa-B ligand (RANKL) on osteoblasts/osteoclasts and by this way improves osteoblast differentiation.
In the same vein, Yamagushi et al. (2011) observed that vitamin K2 induced downregulating NF-κB (cytokine-induced nuclear factorκ) activation in osteoblasts, which is a process independent of carboxylation mechanism .
As illustrated by the results of the studies in vitro, vitamin K (K2 in particular) improves the function of osteoblasts by inducing their proliferation, decreasing their apoptosis, and increasing the expression of osteogenic genes. It also has positive effects on the bone turnover and accordingly regulates bone metabolism.
Effect of vitamin K on osteocyte function also investigated in some in vitro and animal studies. Two osteoporotic rat models demonstrated that vitamin K2 ameliorates adverse effects of glucocorticoid treatment and/or sciatic neurectomy on osteocyte density and lacunar occupancy and had an additive effect on cortical porosity .
In a cell culture study Atkins et al. provided the evidence that vitamin K promotes osteoblast transition to osteocyte. They observed that incubation of human osteoblasts with vitamin K2 in a collagen gel medium increased the number of osteocyte-like cells with elongated cytoplasmic processes. This effect seems to be independent to carboxylation pathway.
Vitamin K2 also has regulatory effect on the transcription of bone markers in murine osteocytes .
Effects of Vitamin K on Bone Resorption and Osteoclast Function
Vitamin K2 treatment has been reported to have an inhibitory effect on osteoclastic bone resorption in murine osteogenic culture , rabbit model, and different rat models .
Vitamin K prevents bone resorption via several mechanisms.
It prevents osteoclast formation either directly or indirectly; that is, it could interfere with the expression of RANKL and upregulates the expression of OPG on osteoclast precursors. In addition, vitamin K decreases both proliferation of tartrate-resistant acid phosphatase positive (TRAP +) cells and TRAP activity in osteogenic culture medium .
Moreover, vitamin K2 inhibits bone resorption, induced by bone resorbing factors such as PGE2, IL1α, and 1, 25(OH) 2D3 in a dose-dependent manner .
Yamaguchi et al. (2011) observed that vitamin K2 downregulated basal and cytokine-induced NF-κB activation in human and murine monocytic cell lines and thereupon prevented the bone resorption.
Activation of NF-κB signal transduction pathway is essential for osteoclast formation. Hara (1995) stated that the inhibitory effect of menaquinones on bone loss was probably independent of the mechanism of action of carboxylation and it was triggered by the side chain of vitamin K2 (geranylgeraniol).
An interesting finding was that such an inhibitory effect was absent in the side chain of vitamin K1 .
Although in vivo and in vitro studies showed the potential of vitamin K2 to induce osteoclast apoptosis, a study on ovariectomized rats revealed that, after MK-4 dietary supplementation (50mg/kg a day), there was a decline in osteoclast bioactivity, yet there was no trace of osteoclast apoptosis .
In sum, the current evidence suggests that vitamin K2 reduces osteoclastic activity via different strategies and that it applies an anabolic effect on the bone.
A 3-year study in 244 postmenopausal women found that those taking vitamin K2 supplements had much slower decreases in age-related bone mineral density.
Long-term studies in Japanese women have observed similar benefits — though very high doses were used in these cases. Out of 13 studies, only one failed to show significant improvement.
Seven of these trials, which took fractures into consideration, found that vitamin K2 reduced spinal fractures by 60%, hip fractures by 77% and all non-spinal fractures by 81%.
In line with these findings, vitamin K supplements are officially recommended for preventing and treating osteoporosis in Japan .
MK-7 and Bone Metabolism
MK-4 enjoys the highest bioactivity among different compounds of menaquinones, and it has been the most extensively studied.
MK-7, however, has higher bioavailability and a longer half-life than vitamin K1 and MK-4. Natto (fermented soy) is a good source of this vitamin produced by Bacillus subtilis and builds a part of the diet in different cultures around the world.
Thus, several studies have exclusively evaluated the effects of this vitamin on the activity of osteoblasts and osteoclasts in human and murine cell culture media.
MK-7 affects bone formation by enhancing the function of osteoblasts.
This compound results in upregulation of SXR target gene, i.e., CYP3A4 in osteoblasts , and induces the synthesis of OPG and OC in osteoblasts. Both of these compounds are osteogenic markers .
Further, MK-7 downregulates NF-κB activation in murine and human osteoblasts and osteoclasts. It was suggested that MK-7 exerts this effect independent of -carboxylation pathway .
May Help Fight Cancer
Cancer is a common cause of death in Western countries.
Worldwide, cancer is the second-leading cause of mortality following cardiovascular disease.
A certain proportion of several cancer types, including colorectal cancer, can only be diagnosed at an advanced stage
However, certain cancer types, such as hepatocellular carcinoma (HCC), can easily recur following a short duration despite effective treatment.
In addition, certain other cancer types are accompanied by severe complications, including failure of the vital organs, despite diagnosis at an early stage and surgery is the contraindication.
Established chemotherapies are not suitable for certain patients.
Hence, the development of a novel therapeutic approach to enhance the overall prognosis of patients with cancer is essential.
Vitamin K (VK) is an essential lipid-soluble vitamin that is comprised of three types, VK1, VK2, and VK3.
VK can activate coagulation factors (factor II, VII, IX, and X), protein C and protein S by facilitating γ-glutamyl carboxylase to catalyze the carboxylation of glutamic acid residues .
In addition, VK-dependent γ-carboxylation has an essential role in maintaining bone homeostasis .
A lack of VK can lead to severe neonatal bleeding and osteoporosis, which can be treated by the clinical application of VK2 .
Previous reports have demonstrated that VK1, VK2 and VK3 can inhibit several neoplastic cell lines at different levels, primarily by inducing apoptosis and cell cycle arrest of cancer cells , including HCC, leukemia, colorectal cancer, ovarian cancer, pancreatic cancer and lung cancer.
Although the inhibition caused by VK3 is highly potent, VK3 is also highly toxic.
By contrast, VK2 is milder, but causes no side effects, whereas VK1 has the least strong function.
Hence, VK2 is a potential chemotherapeutic candidate for the treatment of cancer.
The present review summarizes the results of VK2 against cancer in clinical, animal and in vitro experiments and aims to elucidate the mechanisms of anticancer effects of VK2.
Therefore, finding effective prevention strategies is of utmost importance.
Interestingly, several studies have been done on vitamin K2 and certain types of cancer.
How to Get the Vitamin K2 You Need
Several widely available foods are rich sources of vitamin K1, but vitamin K2 less common.
Your body can partly convert vitamin K1 to K2.
This is useful, as the amount of vitamin K1 in a typical diet is ten times that of vitamin K2.
However, current evidence indicates that the conversion process is inefficient. As a result, you may benefit much more from eating vitamin K2 directly.
Vitamin K2 is also produced by gut bacteria in your large intestine. Some evidence suggests that broad-spectrum antibiotics contribute to K2 deficiency.
Still, the average intake of this important nutrient is incredibly low in the modern diet.
Vitamin K2 is mainly found in certain animal and fermented foods, which most people don’t eat much of.
Rich animal sources include high-fat dairy products from grass-fed cows, egg yolks, as well as liver and other organ meats.
Vitamin K is fat-soluble, which means low-fat and lean animal products don’t contain much of it.
Animal foods contain the MK-4 subtype, while fermented foods like sauerkraut, natto and miso pack more of the longer subtypes, MK-5 to MK-14 .
If these foods are inaccessible to you, taking supplements is a valid alternative.
The benefits of supplementing with K2 may be enhanced even further when combined with a vitamin D supplement, as these two vitamins have synergistic effects.
Though this needs to be studied in more detail, current research on vitamin K2 and health is promising.
In fact, it may have life-saving implications for many people.
Conclusion
There is burden of evidence supporting the osteoprotective effects of vitamin K2 in bone metabolisms.
Vitamins K2, especially MK-4, promotes bone formation by stimulating the differentiation of the osteoblast, regulating the mineralization of the extracellular matrix, upregulating the expression of the bone marker genes, and inhibiting the osteoclastogenesis.
Based on these anabolic properties of vitamin k, it could be suggested that adding vitamin k as an adjunct to the bone materials may stimulate bone cells and their progenitors to produce native bone with promising results.
A recent study has evaluated the behavior of dental pulp stem cells after being exposed to MK-4 in an osteogenic medium.
According to the findings, based on ALP activity and extracellular Ca deposition assay, menaquinone 4 can ameliorate differentiation of dental pulp stem cells into osteoblast and may enhance bone regenerative capacity of cell-based bone tissue engineering therapies . Well-designed RCTs are suggested to determine clinical and histological efficacy of vitamin k on the results of bone augmentation surgeries.
