Abstract
Abstract: Vitamin K (VK) is a fat-soluble vitamin that is indispensable for the activation of vitamin K-dependent proteins (VKDPs). It has been shown to play an important role in the proper calcium deposit at the bone level, hindering that on the vascular walls. The deficiency of this vitamin in European populations is frequent and unknown. It is related to several factors, poor dietary intake, altered intestinal absorption or altered production by bacteria, indicating possible dysbiosis. For Vitamin K2 (VK2), there is currently no official reference daily intake (RDI). However, the effects of VK2 on the improvement of health in cardiovascular diseases, on bone metabolism, on chronic kidney diseases have been the subject of research in recent decades. The microbiota in the gastrointestinal tract plays an important role: Bacteroides are primarily capable of synthetizing very long chain forms of menaquinones and, in addition to the bacteria present in the intestinal flora, VK2 is also produced by bacteria used in food fermentation processes. This review provides an update on the current literature regarding the origin of VK2 and its implications in what is called the “calcium paradox”, namely the lack of calcium in the bone and its storage in the wall of the vessel.
References
1 . The antihaemorrhagic vitamin of the chick. Biochem J. 1935;29(6):1273–85.
2 . Vitamin K in bacteria. Biochim Biophys Acta. 1960;40:208–13.
3 . Supplementary nutrients for prevention of vascular calcification in patients with chronic kidney disease. Korean J Intern Med. 2019;34(3):459–69.
4 . Compilation of a provisional UK database for the phylloquinone (vitamin K1) content of foods. Br J Nutr. 2000;83(4):389–99.
5 . Menaquinone content of cheese. Nutrients. 2018;10(4):446.
6 . Chemistry, nutritional sources, tissue distribution and metabolism of vitamin K with special reference to bone health. J Nutr. 1996;126(4 Suppl):1181S–6S.
7 . Quantitative measurement of tetrahydromenaquinone-9 in cheese fermented by propionibacteria. J Dairy Sci. 2007;90(9):4078–83.
8 . Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis. J Lipid Res. 2014;55(3):345–62.
9 . Determination of vitamin K composition of fermented food. Food Chem. 2019;275:515–22.
10 . Intake of fermented soybean (natto) increases circulating vitamin K2 (menaquinone-7) and gamma-carboxylated osteocalcin concentration in normal individuals. J Bone Miner Metab. 2000;18(4):216–22.
11 . Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood. 2007;109(8):3279–83.
12 . Determination of phylloquinone and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations. Haemostasis. 2000;30(6):298–307.
13 . Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. A double-blind randomised clinical trial. Thromb Haemost. 2015;113(5):1135–44.
14 . Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. 2013;24(9):2499–507.
15 . Production and application of menaquinone-7 (vitamin K2.): a new perspective. World J Microbiol Biotechnol. 2017;33(1):2.
16 . Microbial production of vitamin K2: current status and future prospects. Biotechnol Adv. 2019;107453.
17 Efficient media for high menaquinone-7 production: response surface methodology approach. N Biotechnol. 2011;28(6):665–72.
18 . Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporos Int. 2007;18(7):963–72.
19 Effect of low-dose supplements of menaquinone-7 (vitamin K2) on the stability of oral anticoagulant treatment: dose response relationship in healthy volunteers. J Thromb Haemost. 2013;11(6):1085–92.
20 . Bleeding with anticoagulation therapy – who is at risk, and how best to identify such patients. Thromb Haemost. 2009;102:268–78.
21 Chronic coumarin treatment is associated with increased extracoronary arterial calcificationin humans. Blood. 2010;115(24):5121–3.
22 Obesity, vitamin D status and physical activity: 1,25(OH)2D as a potential marker of vitamin D deficiency in obese subjects. Panminerva Med. 2020;62(2): 83–92. https://doi.org/10.23736/S0031-0808.20.03770-2
23 . The inhibitory roles of vitamin K in progression of vascular calcification. Nutrients. 2020;12(2):583.
24 . Vitamin K: The effect on health beyond coagulation-an overview. Food. Nutr Res. 2012;56.
25 . Vitamin K dependent proteins and the role of vitamin K2 in the modulation of vascular calcification: a review. Oman Med J. 2014;29(3):172–7.
26 . Vitamin K-dependent proteins involved in bone and cardiovascular health. Mol Med Rep. 2018;18(1):3–15.
27 . Vitamin K-dependent matrix GLA protein as multifaceted protector of vascular and tissue integrity. Hypertension. 2019;73:1160–9.
28 Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997;386(6620):78–81.
29 . Keutel syndrome: a review of 50 years of literature. Front Cell Dev Biol. 2021;9:642136.
30 . The effect of menaquinone-7 supplementation on circulating species of matrix Gla protein. Atherosclerosis. 2012;225(2):397–402.
31 . Subclinical atherosclerosis is linked to small intestinal bacterial overgrowth via vitamin K2-dependent mechanisms. World J Gastroenterol. 2017;23(7):1241–9.
32 Novel conformation-specific antibodies against matrixgamma-carboxyglutamicacid (Gla) protein: Undercarboxylated matrix GLA protein as marker for vascular calcification. Arterioscler Thromb Vasc Biol. 2005;25(8):1629–33.
33 . Response of vitamin K status to different intakes and sources of phylloquinone-rich foods: comparison of younger and older adults. Am J Clin Nutr. 1999;70(3):368–77.
34 . Concepts and controversies in evaluating vitamin K status in population-based studies. Nutrients. 2016;8(1):8.
35 . Vitamin K composition of anaerobic gut bacteria. FEMS Microbiol. 1987;41:175–80.
36 Defining a healthy human gut microbiome: current concepts, future directions, and clinical applications. Cell Host Microbe. 2012;12(5):611–22.
37 . Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol. 1977;31:107–33.
38 . Production of menaquinones by intestinal anaerobes. J Infect Dis. 1984;150(2):213–8.
39 Something more to say about calcium homeostasis: the role of vitamin K2 in vascular calcification and osteoporosis. Eur Rev Med Pharmacol Sci. 2013;17(18):2433–40.
40 . Quantitative and qualitative measurements of K vitamins in human intestinal contents. Am J Gastroenterol. 1992;87(3):311–6.
41 . Determination of menaquinone production by Lactococcus spp. and propionibacteria in cheese. Int. Dairy J. 2017;75:1–9.
42 . Distribution of isoprenoid quinone structural types in bacteria and their taxonomic implications. Microbiol Rev. 1981;45(2):316–54.
43 Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature. 2010;468(7320):117–21.
44 . Vitamin K substances and animal feed. FDA Veterinarian Newsletter [Internet]. 2008 [cited 2013 Feb 4]; 23(5): https://www.fda.gov/animal-veterinary/safe-feed/vitamin-k-substances-and-animal-feed.
45 . The mechanism of vascular calcification – a systematic review. Med Sci Monit. 2012;18(1):RA1–RA11.
46 . Osteo/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification. Arterioscler Thromb Vasc Biol. 2003;23(3):489–94.
47 . Human endothelial cells synthesize protein S. Blood. 1986;67(4):1168–71.
48 . Multiple modes of vitamin K actions in aging-related musculoskeletal disorders. Int J Mol Sci. 2019;20(11).
49 The association between vitamin K status and knee osteoarthritis features in older adults: the health, aging and body composition study. Osteoarthritis Cartilage. 2015;23(3):370–8.
50 Gla-rich protein acts as a calcification inhibitor in the human cardiovascular system. Arterioscler Thromb Vasc Biol. 2015;35(2):399–8.
51 Circulating phylloquinone, inactive Matrix Gla protein and coronary heart disease risk: A two-sample Mendelian Randomization study. Clin Nutr. 2020;39(4):1131–6.
52 Matrix Gla protein levels are associated with arterial stiffness and incident heart failure with preserved ejection fraction. Arterioscler Thromb Vasc Biol. 2022;42(2):e61–e73.
53 . The vascular biology of calcification. Semin Dial. 2007;20(2):103–9.
54 . Medial localization of mineralization-regulating proteins in association with Monckeberg’s sclerosis: evidence for smooth muscle cell-mediated vascular calcification. Circulation. 1999;100(21):2168–76.
55 Peripheral vascular calcification in long-emodialysis patients: associated factors and survival consequences. Nephrol Dial Transplant. 2009;24(3):948–55.
56 Progression of aortic calcification is associated with disorders of mineral metabolism and mortality in chronic dialysis patients. Nephrol Dial Transplant. 2011;26(5):1662–9.
57 . Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease? J Am Coll Cardiol. 2002;39(4):695–701.
58 Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004;134(11):3100–5.
59 . Osteocalcin and matrix Gla protein: vitamin K-dependent proteins in bone. Physiol Rev. 1989;69(3):990–1047.
60 . Bone recognition mechanism of porcine osteocalcin from crystal structure. Nature. 2003;425(6961):977–80.
61 . New insights into the biology of osteocalcin. Bone. 2016;82:42–9.
62 . Synthesis of human osteocalcins: gamma-carboxyglutamic acid at position 17 is essential for a calcium-dependent conformational transition. Pept Res. 1994;7(4):171–4.
63 . Age and gender-related changes in the distribution of the ostocalcin in the extracellular matrix of normal male and female bone. J Clin Invest. 1994;93(3):989–97.
64 . The association of serum osteocalcin with the bone mineral density in postmenopausal women. J Clin Diagn Res. 2013;7(5):814–6.
65 . Association of hip fracture incidence and intake of calcium, magnesium, vitamin D, and vitamin K. Eur J Epidemiol. 2008;23(3):219–25.
66 Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2: possible implications for hip-fracture risk. Nutrition. 2001;17(4):315–21.
67 . Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. J Clin Invest. 1993;91(4):1769–74.
68 . Low-dose daily intake of vitamin K (2) (menaquinone-7) improves osteocalcin γ-carboxylation: a double-blind, randomized controlled trials. J Nutr Sci Vitaminol (Tokyo). 2015;61(6):471–80.
69 Japanese 2011 guidelines for prevention and treatment of osteoporosis – executive summary. Arch Osteoporos. 2012;7:3–20.
70 . Does vitamin K2 play a role in the prevention and treatment of osteoporosis for postmenopausal women: a meta-analysis of randomized controlled trials. Osteoporos Int. 2015;26(3):1175–86.
71 . Vascular calcification and bone disease: the calcification paradox. Trends Mol Med. 2009;15(9):405–16.
72 . The association between low bone mass at the menopause and cardiovascular mortality. Am J Med. 1999;106(3):273–8.
73 . Calcium Intake and cardiovascular disease risk: an updated systematic review and meta-analysis. Ann Intern Med. 2016;165:856–66.
74 Lack of evidence linking calcium with or without vitamin D supplementation to cardiovascular disease in generally healthy adults: a clinical guideline from the National Osteoporosis Foundation and the American Society for Preventive Cardiology. Ann Intern Med. 2016;165(12):867–8.
75 . Changes in parameters of bone metabolism in postmenopausal women following a 12-month intervention period using dairy products enriched with calcium, vitamin D, and phylloquinone (vitamin K(1)) or menaquinone-7 (vitamin K (2)): The Postmenopausal Health Study II. Calcif Tissue Int. 2012;90:251–62.
76 . Effect of vitamin K on bone mineral density and fractures in adults: An updated systematic review and meta-analysis of randomised controlled trials. Osteoporos Int. 2019;30:1543–59.
77 . The effect of menaquinone-7 (vitamin K2) supplementation on osteocalcin carboxylation in healthy prepubertal children. Br J Nutr. 2009;102:1171–8.
78 . Low-dose menaquinone-4 improves γ-carboxylation of osteocalcin in young males: A non-placebocontrolled dose-response study. Nutr J. 2014;13:85.
79 . Low-dose vitamin K2 (MK-4) supplementation for 12 months improves bone metabolism and prevents forearm bone loss in postmenopausal Japanese women. J Bone Miner Metab. 2014;32:142–50.