Abstract

In vascular calcification, as a physiological process, intimal arterial calcification (IAC) associated with increased cardiovascular risk is distinguished from medial arterial calcification (MAC) localized mainly in the lamina elatica interna, which are not only based on different pathophysiological mechanisms. They also lead to different cardiovascular diseases.

While intimal arterial calcification involves inflammation and lipid accumulation, a calcification process similar to desmal ossification plays the main role in medial arterial calcification. In this context, the phenotype change of smooth muscle cells from muscular type to synthesizing form in the tunica media is considered to be of great importance, which puts the matrix GLA protein, mainly involved in bone metabolism, in the center of interest. The present review work elucidates the molecular biological basis of interaction of matrix GLA protein subunits in the pathogenesis of vascular calcifications and the influence of diet on the consequences of underactivation of matrix GLA protein.

References

1. Ghosh S, Luo D, He W, et al. Diabetes and calcification: The potential role of anti-diabetic drugs on vascular calcification regression. Pharmacological Research, 2020; 158. doi.org/10.1016/j.phrs.2020.104861.
2. Liakopoulos V, Roumeliotis S, Gorny X, Dounousi E, Mertens PR. Oxidative stress in hemodialysis patients: A review of the literature. Oxid Med Cell Longev, 2017: 3081856. doi: 10.1155/2017/3081856.
3. Liakopoulos V, Roumeliotis S, Zarogiannis S, Eleftheriadis T, Mertens PR. Oxidative stress in hemodialysis: Causative mechanisms, clinical implications, and possible therapeutic interventions. Semin Dial, 2019; 58-71. doi.org/10.1111/sdi.12745.
4. Nelson AJ, Raggi P, Wolf M, Gold AM, Chertow GM, Roe MT. Targeting Vascular Calcification in Chronic Kidney Disease, 2020; 5(4): doi.org/10.1016/j.jacbts.2020.02.002.
5. Brinck U, Mirzaie M, Korabiowska M, Meyer T. Expression rate of vinculin isoforms in human aortocoronary saphenous vein grafts. Int J Cardiol, 1997; 125-132. doi.org/10.1016/S0167-5273(97)02919-7.
6. Virchow R. Cellular pathology. As based upon physiological and pathological histology. Lecture XVI-Atheromatous affection of arteries. Nutr Rev, 1989; 47:23–25. doi: 10.1111/j.1753-4887.1989.tb02747.x.
7. Mori H, Torii S, Kutyna M, Sakamoto A, Finn AV, Virmani R, Coronary Artery Calcification and its Progression: What Does it Really Mean? JACC: Cardiovascular Imaging, 2018; 11(1): 127-142. doi.org/10.1016/j.jcmg.2017.10.012.
8. Zwakenberg SR, de Jong PA, Hendriks EJ, et al. Intimal and medial calcification in relation to cardiovascular risk factors. PLoS ONE, 2020; 15(7): e0235228. doi:10.1371/journal.pone.0235228.
9. Lanzer P, Boehm M, Sorribas V, et al. Medial vascular calcification revisited: review and perspectives. Eur Heart J, 2014; 14; 35(23): 1515-1525. doi: 10.1093/eurheartj/ehu163.
10. Adar A, Onalan O, Keles Hb, Cakan F, Kokturk U. Relationship between Aortic Arch Calcification, Detected by Chest X-Ray, and Renal Resistive Index in Patients with Hypertension. Med Princ Pract, 2019; 28: 133–140. doi.org/10.1159/000495786.
11. Koupenova M, Kehrel BE, Corkrey HA, Freedman JE. Thrombosis and platelets: an update. Europ Heart J, 2017; 38(11): 785–791. doi.org/10.1093/eurheartj/ehw550.
12. Marshall AP, Lu0 W, Wang Xl, et al. Medial artery calcification increases neointimal hyperplasia after balloon injury. Sci Rep, 2019; 9, 8193. doi.org/10.1038/s41598-019-44668-4.
13. Lin X, Zhu T, Xu F, et al. Plasma Exosomes Derived From Patients With End-Stage Renal Disease and Renal Transplant Recipients Have Different Effects on Vascular Calcification. Front Cell Dev Biol, 2021. doi.org/10.3389/fcell.2020.618228.
14. Hendriks EJE, Beulens JWJ, Mali WPTM, et al. Breast Arterial Calcifications and Their Association With Incident Cardiovascular Disease and Diabetes. J Am Coll Cardiol, 2015; 65(8):859–60. doi: 10.1016/j.jacc.2014.12.015.
15. Yoo JH, Kim JG, Chung K, et al. Vascular Calcification in Patients Undergoing Total Knee Arthroplasty: Frequency and Effects on the Surgery. Clin Orthop Surg, 2020; 12(2):171-177. doi.org/10.4055/cios19125.
16. Mirzaie M, Guliyev Z, Schultz M, Schwartz P, Addicks JP, ShFatehpur S. Evidence of woven bone formation in carotid artery Plaques. J Cardiol Cardiovasc Med, 2021;6: 001-006. doi: 10.29328/journal.jccm.1001108.
17. Hoek AG, Zwakenberg SR, Elders PJM, et al. An elevated ankle-brachial index is not a valid proxy for peripheral medial arterial calcification. Atherosclerosis, 2021; 323: 13-19. doi.org/10.1016/j.atherosclerosis.2021.03.010.
18. Lee SJ, Lee IK, Jeon JH. Vascular Calcification-New Insights into Its Mechanism. Int. J. Mol. Sci. 2020, 21, 2685; doi:10.3390/ijms21082685.
19. Wu X, Geng YJ, Chen Z, et al. Coron Artery Dis, 2019; 30(4):297-302. doi: 10.1097/MCA.0000000000000739.
20. O’Neill WC, Han KH, Schneider TM, Hennigar RA. Prevalence of nonatheromatous lesions in peripheral arterial disease. Arterioscler Thromb Vasc Biol, 2015; 35(2):439-447. doi: 10.1161/ATVBAHA.114.304764.
21. Madhavan MV, Tarigopula M, Mintz GS, Maehara A, Stone GW, Généreux P. Coronary artery calcification: pathogenesis and prognostic implications. J Am Coll Cardiol, 2014; 63(17):1703–1714. doi: 10.1016/j.jacc.2014.01.017.
22. Wen L, Chen J, Duan L, LiS. Vitamin K‑dependent proteins involved in bone and cardiovascular health (Review). Mol Med Rep, 2018; 18(1): 3-15. doi.org/10.3892/mmr.2018.8940.
23. Lin X, Patil S, Gao YG, Qian A. The Bone Extracellular Matrix in Bone Formation and Regeneration. Front Pharmacol, 2020. doi.org/10.3389/fphar.2020.00757
24. Zhang M, Ishikawa S, Inagawa T, et al. Influence of Mechanical Force on Bone Matrix Proteins in Ovariectomised Mice and Osteoblast-like MC3T3-E1 Cells. In Vivo, 2017; 31(1): 87-95. doi: 10.21873/invivo.11029.
25. Bäck M, Aranyi T, Cancela ML, et al. Endogenous Calcification Inhibitors in the Prevention of Vascular Calcification: A Consensus Statement From the COST Action EuroSoftCalcNet. Front Cardiovasc, 2019. doi.org/10.3389/fcvm.2018.00196.
26. Perrone E, Chen K, Ramos M, et al. A Novel MGP Gene Mutation Causing Keutel Syndrome in a Brazilian Patient. Mol Syndromol, 2018; 9:159-163. doi.org/10.1159/000488573.
27. Cancel ML, Laizé V, Conceição N, Kempf H, Murshed M. Keutel Syndrome, a Review of 50 Years of Literature. Front Cell Dev Biol, 2021. /doi.org/10.3389/fcell.2021.642136.
28. Roumeliotis S, Dounousi E, Salmas M, , Eleftheriadis T, Liakopoulos V. Vascular Calcification in Chronic Kidney Disease: The Role of Vitamin K- Dependent Matrix Gla Protein. Front Med, 2020. doi.org/10.3389/fmed.2020.00154.
29. Robey PG, Boskey AL, Leikin S. Chapter 8 - The regulatory role of matrix proteins in mineralization of bone. Editor(s): David W. Dempster, Jane A. Cauley, Mary L. Bouxsein, Felicia Cosman, Marcus and Feldman's Osteoporosis (Fifth Edition), Academic Press, 2021: 165-187. doi.org/10.1016/B978-0-12-813073-5.00008-3.
30. Basic-Jukic N, Gulin M, Hudolin T, Kastelan Z. Expression of BMP-2 in Vascular Endothelial Cells of Recipient May Predict Delayed Graft Function After Renal Transplantation. Kidney Blood Press Res, 2016; 41:781-793. doi.org/10.1159/000450568.
31. Leurs N, Martinand-Mari C, Ventéo S, Haitina T, Debiais-Thibaud M. Evolution of Matrix Gla and Bone Gla Protein Genes in Jawed Vertebrates. Front Genet, 2021. doi.org/10.3389/fgene.2021.620659.
32. Wyatt CM, Drueke TB. Vascular calcification in chronic kidney disease: here to stay?
33. Nephro Digest Chronic Kidney Dis, 2017; 92(2): 276-278. doi.org/10.1016/j.kint.2017.05.019.
34. Wa Q, Liu Y, Huang Y, et al. miRNA-140 inhibits C3H10T1/2 mesenchymal stem cell proliferation by targeting CXCL12 during transforming growth factor-β3-induced chondrogenic differentiation. Mol Med Rep, 2017; 16(2): 1389-1394. doi.org/10.3892/mmr.2017.6720.
35. Kuronuma K, Yokoi A, a Fukuoka T, et al. Matrix Gla protein maintains normal and malignant hematopoietic progenitor cells by interacting with bone morphogenetic protein-4, Heliyon, 2020; 6(4): e03743. doi.org/10.1016/j.heliyon.2020.e03743.
36. Roumeliotis S, Dounousi E, Eleftheriadis T, Liakopoulos V. Association of the Inactive Circulating Matrix Gla Protein with Vitamin K Intake, Calcification, Mortality, and Cardiovascular Disease: A Review. Int. J Mol Sci, 2019; 20(3): 628. doi.org/10.3390/ijms20030628.
37. Suzuki H, Tatei K, Ohshima N, Sato S, Izumi T. Extracellular matrix mineralization in the mouse osteoblast-like cell line MC3T3-E1 is regulated by actin cytoskeleton reorganization and non-protein molecules secreted from the cells themselves. BioRxiv, 2019. doi: https://doi.org/10.1101/551531.
38. Shea MK, L Booth SL. Vitamin K, Vascular Calcification, and Chronic Kidney Disease: Current Evidence and Unanswered Questions. Curr Dev Nutr, 2019; 3(9): nzz077. doi: 10.1093/cdn/nzz077.
39. Zhu M, Zeng F, Cui Y, Liu X, Chen H. Expression of matrix Gla protein and bone morphogenetic protein 2 in renal papillary tissues in patients with calcium oxalate kidney stones. Journal of Central South University (Medical Sciences), 2017; (12): 277-283. doi: 10.11817/j.issn.1672-7347.2017.03.007.
40. Mayer O, Seidlerová J, Bruthans J, et al. Desphospho-uncarboxylated matrix Gla-protein is associated with mortality risk in patients with chronic stable vascular disease. Athreosclerosis, 2014; 235(1): 162-168. doi.org/10.1016/j.atherosclerosis.2014.04.027.
41. Saad AAEA, Kenawy EM, Elashakr AM et al. Effect of vitamin K1 supplementation on matrix Gla protein level and vascular calcification in hemodialysis patients. Egypt J Intern Med, 2017; 29: 5–10. doi.org/10.4103/1110-7782.207779.
42. WeicX, Su Y, Li Q, Zheng Z, Hou P. Analysis of crucial genes, pathways and construction of the molecular regulatory networks in vascular smooth muscle cell calcification. Exp Thera Med, 2021, 21(6): 589. doi.org/10.3892/etm.2021.10021.
43. Canet-Soulas E, Bessueille L, Mechtouff L, Magne D. The Elusive Origin of Atherosclerotic Plaque Calcification. Front Cell Dev, 2021. doi.org/10.3389/fcell.2021.622736.
44. Zwakenberg SR, van der Schouw YT, Vermeer Cb, Pasterkamp G, den Ruijter HM, Beulens JWJ. Matrix Gla Protein, Plaque Stability, and Cardiovascular Events in Patients with Severe Atherosclerotic Disease. Cardiology, 2018; 141:32–36. doi.org/10.1159/000493006.
45. Tesfamariam B. Involvement of Vitamin K-Dependent Proteins in Vascular Calcification. J Cardiovasc Pharmacol Ther, 2019; 24(4): 323-333. doi: 10.1177/1074248419838501.
46. Rennenberg RJ, de Leeuw PW, Kessels AG, et al. Calcium scores and matrix Gla protein levels: association with vitamin K status. Eur J Clin Invest. 2010 Apr; 40(4): 344-349. doi: 10.1111/j.1365-2362.2010.02275.x.
47. Dalmeijer GW, van der Schouw YT, Magdeleyns EJ, et al. Circulating species of matrix Gla protein and the risk of vascular calcification in healthy women. Int J Cardiol, 2013; 168(6): e168-70. doi: 10.1016/j.ijcard.2013.08.062.
48. Parker BD, Schurgers LJ, Brandenburg VM, et al. The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Ann Intern Med, 2010; 152(10):640-648. doi: 10.1059/0003-4819-152-10-201005180-00004.
49. Nigwekar SU, Bloch DB, Nazarian RM, et al. Vitamin K-Dependent Carboxylation of Matrix Gla Protein Influences the Risk of Calciphylaxis. J Am Soc Nephrol, 2017; 28(6): 1717-1722. doi: 10.1681/ASN.2016060651.
50. Kurnatowska I, Grzelak P, Masajtis-Zagajewska A, et al. Plasma Desphospho-Uncarboxylated Matrix Gla Protein as a Marker of Kidney Damage and Cardiovascular Risk in Advanced Stage of Chronic Kidney Disease. Kidney Blood Press Res, 2016; 41:231-239. doi.org/10.1159/000443426.
51. Jaminon AMG, Dai L, Qureshi AR, et al. Matrix Gla protein is an independent predictor of both intimal and medial vascular calcification in chronic kidney disease. Sci Rep, 2020; 10, 6586. doi.org/10.1038/s41598-020-63013-8.
52. Jeannin AC, Salem JE,, Massy Z, et al. Inactive matrix gla protein plasma levels are associated with peripheral neuropathy in Type 2 diabetes. PloS One, 2020; doi.org/10.1371/journal.pone.0229145.
53. Ossareh S, Marghoob B, Bayat R. Relationship between Fetuin-A and vascular or valvular calcification in hemodialysis patients. J Clini Nephrol. 2019; 3: 001-011. DOI: 10.29328/journal.jcn.1001021.
54. Delanaye P, Krzesinski JM, Warling X, et al. Dephosphorylated-uncarboxylated Matrix Gla protein concentration is predictive of vitamin K status and is correlated with vascular calcification in a cohort of BMC Nephrol, 2014; 15:145. doi: 10.1186/1471-2369-15-145.
55. Griffin TP, Islam MN, Wall D, et al. Plasma dephosphorylated-uncarboxylated Matrix Gla-Protein (dp-ucMGP): reference intervals in Caucasian adults and diabetic kidney disease biomarker potential. Sci Rep, 2019; 9: 18452. doi.org/10.1038/s41598-019-54762-2.
56. Ketteler M, Brandenburg VM. K-alcification Protection in Dialysis Patients: The Underestimated Phenomenon of Vitamin K Deficiency. JASN, 2017; 28(6): 1667-1668. doi.org/10.1681/ASN.2017020180.
57. Roumeliotis S, Roumeliotis A, Panagoutsos S, et al. Matrix Gla protein T-138C polymorphism is associated with carotid intima media thickness and predicts mortality in patients with diabetic nephropathy. J Diabetes Complications, 2017; 31(10):1527-1532. doi: 10.1016/j.jdiacomp.2017.06.012.
58. Ueland T, Gullestad L, Dahl CP, et al. Undercarboxylated matrix Gla protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis. J Intern Med, 2010; 268(5): 483-492. doi: 10.1111/j.1365-2796.2010.02264.x.
59. Shea MK, O’Donnell CJ, Vermeer C, et al. Circulating uncarboxylated matrix gla protein is associated with vitamin K nutritional status, but not coronary artery calcium, in older adults. J Nutr, 2011; 141: 1529–1534. doi: 10.3945/jn.111.139634.
60. Pivin E, Ponte B, Pruijm M, et al. Inactive matrix Gla-protein is associated with arterial stiffness in an adult population-based study. Hypertension, 2015; 66:85–92. doi: 10.1161/HYPERTENSIONAHA.115.05177.
61. Knapen MH, Braam LA, Drummen NE, et al. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. A double-blind randomised clinical trial. Thromb Haemost, 2015; 113:1135–1144. doi: 10.1160/TH14-08-0675.
62. Mayer O, Jr, Seidlerova J, Wohlfahrt P, et al. Desphospho-uncarboxylated matrix Gla protein is associated with increased aortic stiffness in a general population. J Hum Hypertens, 2016; 30(7):418-23. doi: 10.1038/jhh.2015.55.
63. Aoun M, Makki M, Azar H, Matta H, Chelala DN. High dephosphorylated-uncarboxylated MGP in hemodialysis patients: Risk factors and response to vitamin K2, A pre-post intervention clinical trial. BMC Nephrol, 2017; 18:191. doi: 10.1186/s12882-017-0609-3.
64. Ueland T, Gullestad L, Dahl CP, et al. Undercarboxylated matrix Gla protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis. J Intern Med, 2010; 268:483–492. doi: 10.1111/j.1365-2796.2010.02264.x.
65. Ueland T, Dahl CP, Gullestad L, et al. Circulating levels of non-phosphorylated undercarboxylated matrix Gla protein are associated with disease severity in patients with chronic heart failure. Clin Sci (Lond), 2011; 121:119–127. doi: 10.1042/CS20100589.
66. Mayer O, Seidlerová J, Vaněk J, et al. The abnormal status of uncarboxylated matrix Gla protein species represents an additional mortality risk in heart failure patients with vascular disease. Int J Cardiol, 2016; 203: 916–922. doi: 10.1016/j.ijcard.2015.10.226
67. Dalmeijer GW, van der Schouw YT, Magdeleyns EJ, et al. Matrix Gla protein species and risk of cardiovascular events in type 2 diabetic patients. Diabetes Care, 2013; 36:3766–3771. doi: 10.2337/dc13-0065.
68. Mayer O, Seidlerová J, Bruthans J, et al. Desphospho-uncarboxylated matrix Gla-protein is associated with mortality risk in patients with chronic stable vascular disease. Atherosclerosis, 2014; 235:162–168. doi: 10.1016/j.atherosclerosis.2014.04.027.
69. Keyzer CA, Vermeer C, Joosten MM, et al. Vitamin K status and mortality after kidney transplantation: a cohort study. Am J Kidney Dis, 2015; 65:474–483. doi: 10.1053/j.ajkd.2014.09.014.
70. Liu YP, Gu YM, Thijs L, et al.. Inactive matrix Gla protein is causally related to adverse health outcomes: a Mendelian randomization study in a Flemish population. Hypertension, 2015; 65:463–470. doi: 10.1161/HYPERTENSIONAHA.114.04494.
71. Riphagen IJ, Keyzer CA, Drummen NEA, et al. Prevalence and effects of functional vitamin K insufficiency: the PREVEND study. Nutrients. 2017; 9:e1334. doi: 10.3390/nu9121334.
72. Van den Heuvel EG, van Schoor NM, Lips P, et al. Circulating uncarboxylated matrix Gla protein, a marker of vitamin K status, as a risk factor of cardiovascular disease. Maturitas, 2014; 77:137–141. doi: 10.1016/j.maturitas.2013.10.008.
73. wie FF, Trenson S, Verhamme P, Vermeer C, Staessen JA. Vitamin K–Dependent Matrix Gla Protein as Multifaceted Protector of Vascular and Tissue Integrity. Hypertension, 2019; 73(6): 1160–1169. doi: 10.1161/HYPERTENSIONAHA.119.12412.
74. Castiglione V, Pottel H, Lieske JC, et al. Evaluation of inactive Matrix-Gla-Protein (MGP) as a biomarker for incident and recurrent kidney stones. J Nephrol, 2020; 33(1): 101-107. soi: 10.1007/s40620-019-00623-0.
75. Bermudez JY, Webber HC, Brown B, Braun TA, Clark AF, Mao W. A Comparison of Gene Expression Profiles between Glucocorticoid Responder and Non-Responder Bovine Trabecular Meshwork Cells Using RNA Sequencing. PloSOne, 2017. doi.org/10.1371/journal.pone.0169671.
76. Borrás T, Smith MH, Buie LK. A novel Mgp-Cre knock-in mouse reveals an anticalcification/antistiffness candidate gene in the trabecular meshwork and peripapillary scleral region. Invest Ophthalmol Vis Sci, 2015; 56: 2203–2214. doi: 10.1167/iovs.15-16460.
77. Brnic D, Martinovic D, Zivkovic PM, et al. Inactive matrix Gla protein is elevated in patients with inflammatory bowel disease. World J Gastroenterol, 2020; 26(32): 4866-4877. doi: 10.3748/wjg.v26.i32.4866.
78. Asokan P, Mitra RN, Periasamy R, Han Z, Borrás T. A naturally fluorescent Mgp transgenic mouse for angiogenesis and glaucoma longitudinal studies. Invest Ophthalmol Vis Sci, 2018; 59:746–756. doi: 10.1167/iovs.17-22992.
79. Patel G, Fury W, Yang H, et al. Molecular taxonomy of human ocular outflow tissues defined by single-cell transcriptomics. PNAS, 2020; 117(23): 12856-12867. doi.org/10.1073/pnas.2001896117.
80. Zheng W, Li Q, Zhao C, Da Y, ZhangHL, Chen Z et al. Differentiation of Glial Cells From hiPSCs: Potential Applications in Neurological Diseases and Cell Replacement Therapy. Front Cell Neurosci, 2018. doi.org/10.3389/fncel.2018.00239.
81. Abdolrahimzadeh S, Felli L, Piraino DC et al. Retinal microvascular abnormalities overlying choroidal nodules in neurofibromatosis type 1. BMC Ophthalmol, 2014; 14, 146. doi.org/10.1186/1471-2415-14-146.
82. Yatsuya H, Folsom AR, Wong TY, Klein R, Klein BE, Sharrett AR; ARIC Study Investigators. Retinal microvascular abnormalities and risk of lacunar stroke: Atherosclerosis Risk in Communities Study. Stroke, 2010; 41:1349–1355. doi: 10.1161/STROKEAHA.110.580837.
83. Lin F, Zhu P, Huang F et al. Aortic stiffness is associated with the central retinal arteriolar equivalent and retinal vascular fractal dimension in a population along the southeastern coast of China. Hypertens Res, 2015; 38: 342–348 (2015). https://doi.org/10.1038/hr.2015.11.
84. Zwakenberg SR, Burgess S, Sluijs I, et al. Circulating phylloquinone, inactive Matrix Gla protein and coronary heart disease risk: A two-sample Mendelian Randomization study Clin Nutr, 2020; 39(4):1131-1136. doi: 10.1016/j.clnu.2019.04.024.
85. Liu YP, Gu YM, Thijs L, et al. Inactive matrix Gla protein is causally related to adverse health outcomes: a Mendelian randomization study in a Flemish population. Hypertension, 2015; 65(2):463-70. doi: 10.1161/HYPERTENSIONAHA.114.04494.
86. Dalmeijer GW, van der Schouw YT, Magdeleyns EJ, et al. Circulating desphospho-uncarboxylated matrix γ-carboxyglutamate protein and the risk of coronary heart disease and stroke. J Thromb Haemost, 2014; 12(7):1028-1034. doi: 10.1111/jth.12609.
87. Zwakenberg SR, Remmelzwaal S, Beulens JWJ, et al. Circulating Phylloquinone Concentrations and Risk of Type 2 Diabetes: A Mendelian Randomization Study. Diabetes, 2019; 68(1): 220-225. doi: 10.2337/db18-0543.
88. Shea MK, O'Donnell CJ, Vermeer C, et al. 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):1529-1534. doi: 10.3945/jn.111.139634.
89. Caluwé R, Verbeke F, De Vriese AS. Evaluation of vitamin K status and rationale for vitamin K supplementation in dialysis patients. Nephrol Dial Transplant, 2020; 35(1):23-33. doi: 10.1093/ndt/gfy373.
90. Willems BA, Vermeer C, Reutelingsperger CP, Schurgers LJ. The realm of vitamin K dependent proteins: shifting from coagulation toward calcification. Mol Nutr Food Res. 2014; 58:1620–1635. doi: 10.1002/mnfr.201300743.
91. Manolagas SC. Osteocalcin promotes bone mineralization but is not a hormone. PLoS Genet, 2020; 16(6): e1008714. doi.org/10.1371/journal.pgen.1008714.
92. Levinger I, Brennan-Speranza TC, Zulli A, et al. Multifaceted interaction of bone, muscle, lifestyle interventions and metabolic and cardiovascular disease: role of osteocalcin. Osteoporos Int, 2017; 28:2265–2273. doi: 10.1007/s00198-017-3994-3.
93. Geissler K, Jäger E, Barna A, et al. Molecular Basis and Clinical Application of Growth-Factor-Independent In Vitro Myeloid Colony Formation in Chronic Myelomonocytic Leukemia. Int J Mol Sci, 2020; 21(17): 6057. doi.org/10.3390/ijms21176057.
94. Cranenburg ECM, Schurgers LJ. Vermeer C. Vitamin K: The coagulation vitamin that became omnipotent. Thromb Haemost, 2007; 98(01): 120-125. doi: 10.1160/TH07-04-0266.
95. Alappan HR, Kaur G, Manzoor S, Navarrete J, O’Neill WC. Warfarin Accelerates Medial Arterial Calcification in Humans. Arterioscler Thromb Vasc Biol, 2020; 40:1413–1419. doi.org/10.1161/ATVBAHA.119.313879.
96. Cranenburg EC, Koos R, Schurgers LJ, et al. Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species.Thromb Haemost, 2010; 104:811–822. doi: 10.1160/TH09-11-0786.
97. Dahlberg S, Nilsson CU, Kander T, Schott U. Vitamin K: Nutrition, Metabolism and Current Evidence from Clinical Trials. Nutr Metab Open Acc, 2018: 101. doi:10.29011/NMOA-101/100001.
98. Dauti F, Hjaltalin Jonsson M, Hillarp A, Bentzer P, Schott U. Perioperative changes in PIVKA-II. Scand J Clin Lab Invest, 2015; 75: 562-567. doi: 10.3109/00365513.2015.1058521.
99. Dahlberg S, Nilsson CU, Kander T, Schott U. Detection of subclinical vitamin K deficiency in neurosurgery with PIVKA-II. Scand J Clin Lab Invest, 2017; 77: 267-274. doi: 10.1080/00365513.2017.1303190.
100. Theuwissen E, Magdeleyns EJ, Braam LA, et al. Vitamin K status in healthy volunteers. Food Funct 5: 229-234. Food Funct, 2014; 5(2):229-234. doi: 10.1039/c3fo60464k.
101. O'Connor EM, Grealy G, McCarthy J, et al. Effect of phylloquinone (vitamin K1) supplementation for 12 months on the indices of vitamin K status and bone health in adult patients with Crohn's disease. Br J Nutr, 2014; 11287): 1163–1174. doi: https://doi.org/10.1017/S0007114514001913.
102. Kriegermeier A, Green R. Pediatric Cholestatic Liver Disease: Review of Bile Acid Metabolism and Discussion of Current and Emerging Therapies. Front Med, 2020: doi.org/10.3389/fmed.2020.00149.
103. Kaesler N, Magdeleyns E, Herfs M, et al. Impaired vitamin K recycling in uremia is rescued by vitamin K supplementation. Kidney Int, 2014; 86: 286-293. doi: 10.1038/ki.2013.530.
104. McCabe KM, Adams MA, Holden RM. Vitamin K status in chronic kidney disease. Nutrients, 2015; 5: 4390-4398. 10.3390/nu5114390.
105. 103 Araki S, Shirahata A. Vitamin K Deficiency Bleeding in Infancy. Nutrients 2020, 12, 780; doi:10.3390/nu12030780.
106. Ivanov DO. History of the study of hemorrhagic disease of newborns. Pediatrician (St. Petersburg), 2017: 8(4): 118-125. doi: 10.17816/PED84118-125.
107. Obladen M. Early Neonatal Special Care Units and Their Scientific Achievements. Neonatology, 2012;102:89-97. doi: 10.1159/000336285.
108. Dituri F, Buonocore G, Pietravalle A, et al. PIVKA-II plasma levels as markers of subclinical vitamin K deficiency in term infants. J Matern Fetal Neonatal Med, 2012; 25(9):1660-1663. doi: 10.3109/14767058.2012.657273.
109. Ceratto, S, Savino F. Vitamin K deficiency bleeding in an apparently healthy newborn infant: the compelling need for evidence-based recommendation. Ital J Pediatr, 2019; 45, 30. doi.org/10.1186/s13052-019-0625-y.
110. Marchili MR, Santoro E, Marchesi A, et al. Vitamin K deficiency: a case report and review of current guidelines. Ital J Pediatr, 2018; 44: 36. doi.org/10.1186/s13052-018-0474-0.
111. McPherson C. Vitamin K Deficiency Bleeding: An Ounce of Prevention. Neonatal Network, 2018; 39(6). doi: 10.1891/0730-0832/11-T-630.
112. Elango K, Javaid A, Khetarpal BK et al. The Effects of Warfarin and Direct Oral Anticoagulants on Systemic Vascular Calcification: A Review. Cells, 2021; 10, 773. doi.org/10.3390/cells10040773.
113. Lin MC, Streja E, Soohoo M, Hanna M, Savoj J, Kalantar-Zadeh K, Lau W, L. Warfarin Use and Increased Mortality in End-Stage Renal Disease. Am J Nephrol, 2017; 46:249-256. doi: 10.1159/000481207.
114. Asemi Z, RayganF, Bahmani F, et al. The effects of vitamin D, K and calcium co-supplementation on carotid intima-media thickness and metabolic status in overweight type 2 diabetic patients with CHD. British Journal of Nutrition, 2016; 116: 286–293. doi:10.1017/S0007114516001847.
115. Bartstra JW, Draaisma F, Zwakenberg SR et al. Six months vitamin K treatment does not affect systemic arterial calcification or bone mineral density in diabetes mellitus 2. Eur J Nutr, 2021; 60: 1691–1699. doi.org/10.1007/s00394-020-02412-z.
116. Popa DS, Bigman, G, Rusu ME. The Role of Vitamin K in Humans: Implication in Aging and Age-Associated Diseases. Antioxidants, 2021; 10, 566. doi.org/10.3390/antiox10040566.
117. Dai L, Li L, Erlandsson H, et al. (2021) Functional vitamin K insufficiency, vascular calcification and mortality in advanced chronic kidney disease: A cohort study. PLoS ONE, 2021; 16(2): e0247623. doi.org/10.1371/journal.pone.0247623.
118. Nakanishi T, Kuragano T (eds): CKD-Associated Complications: Progress in the Last Half Century. Contrib Nephrol. Basel, Karger, 2019; 198: 62–72. doi: 10.1159/000496532). doi: 10.1159/000496532.
119. De Vriese AS, Caluwé R, Pyfferoen L, et al. Multicenter Randomized Controlled Trial of Vitamin K Antagonist Replacement by Rivaroxaban with or without Vitamin K2 in Hemodialysis Patients with Atrial Fibrillation: the Valkyrie Study. JASN, 2020; 31(1): 186-196. doi.org/10.1681/ASN.2019060579.
120. Lindholt JS, Frandsen NE, Fredgart MH, et al. Effects of menaquinone-7 supplementation in patients with aortic valve calcification: study protocol for a randomised controlled trial. BMJ Open, 2018; 8:e022019. doi:10.1136/bmjopen-2018-022019.
121. Saad AAEA, Kenawy EM, Elashakr AM et al. Effect of vitamin K1 supplementation on matrix Gla protein level and vascular calcification in hemodialysis patients. Egypt J Intern Med, 2017; 29: 5–10. doi.org/10.4103/1110-7782.207779.
122. Mott A, Bradley T, Wright K et al. 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: 1543–1559. doi.org/10.1007/s00198-019.
123. van Ballegooijen AJ, Beulens JWJ, Schurgers LJ, et al. Effect of 6-Month Vitamin D Supplementation on Plasma Matrix Gla Protein in Older Adults. Nutrients, 2019; 11(2): 231. doi: 10.3390/nu11020231.
124. Hou YC, LU CH, Zheng CM, et al. Emerging Role of Vitamins D and K in Modulating Uremic Vascular Calcification: The Aspect of Passive Calcification. Nutrients, 2019; 11(1): 152. doi.org/10.3390/nu11010152.
125. van Ballegooijen, AJ, Beulens J.WJ, Kieneker LM, et al. Combined low vitamin D and K status amplifies mortality risk: a prospective study. Eur J Nutr, 2021; 60: 1645–1654. doi.org/10.1007/s00394-020-02352-8.
126. Florea A, Kooi ME, Mess W, Schurgers LJ, Bucerius J, Mottaghy FM. Effects of Combined Vitamin K2 and Vitamin D3 Supplementation on Na[18F]F PET/MRI in Patients with Carotid Artery Disease: The INTRICATE Rationale and Trial Design. Nutrients, 2021; 13(3): 994. doi.org/10.3390/nu13030994.
127. Ambrożewicz E, Muszyńska M, Tokajuk G, Grynkiewicz G, Žarković N, E Skrzydlewska. Beneficial Effects of Vitamins K and D3 on Redox Balance of Human Osteoblasts Cultured with Hydroxyapatite-Based Biomaterials. Cells, 2019; 8(4): 325. doi.org/10.3390/cells8040325
128. Van de Peppel J, van Leeuwen JPTM. Vitamin D and gene networks in human osteoblasts. Front Physiol. 2014;5:137. doi:10.3389/fphys.2014.00137.
129. Cianciolo G, La Manna G, Della Bella E. Effect of Vitamin D Receptor Activator Therapy on Vitamin D Receptor and Osteocalcin Expression in Circulating Endothelial Progenitor Cells of Hemodialysis Patients. Blood Purif, 2013;35:187-195. doi.org/10.1159/000347102.
130. Zittermann A, Ernst JB, Prokop S, et al. Effect of vitamin d on all-cause mortality in heart failure (evita): A 3-year randomized clinical trial with 4000 iu vitamin d daily. Eur Heart J, 2017;38: 2279–2286. doi: 10.1093/eurheartj/ehx235.
131. Barbarawi M, Kheiri B, Zayed Y, et al. Vitamin D Supplementation and Cardiovascular Disease Risks in More Than 83 000 Individuals in 21 Randomized Clinical Trials: A Meta-analysis. JAMA Cardiol, 2019; 4(8): 765–776. doi:10.1001/jamacardio.2019.1870.
132. Thiele I, Linseisen J, Meisinger C, et al. Associations between calcium and vitamin d supplement use as well as their serum concentrations and subclinical cardiovascular disease phenotypes. Atherosclerosis, 2015; 241:743–751. doi: 10.1016/j.atherosclerosis.2015.06.032.
133. Challoumas D, Stavrou A, Pericleous A, Dimitrakakis G. Effects of combined vitamin d--calcium supplements on the cardiovascular system: Should we be cautious? Atherosclerosis. 2015;238:388–398. doi: 10.1016/j.atherosclerosis.2014.12.050.
134. Zhang D, Li S, Zhang Z, et al. Urinary stone composition analysis and clinical characterization of 1520 patients in central China. Sci Rep, 2021; 11, 6467. doi.org/10.1038/s41598-021-85723-3.
135. Kahwati LC, Weber RP, Pan H, et al. Vitamin d, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: Evidence report and systematic review for the us preventive services task force. JAMA, 2018; 319:1600–1612. doi: 10.1001/jama.2018.3185.
136. Bolland MJ, Grey A, Avenell A. Effects of vitamin D supplementation on musculoskeletal health: A systematic review, meta-analysis, and trial sequential analysis. Lancet Diabetes Endocrinol, 2018; 6:847–858. doi:10.1016/S2213-8587(18)30265-1.
137. Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev, 2014; 7:CD007470. doi: 10.1002/14651858.CD007470.pub3.
138. Avenell A, Mak JC, O’Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. Cochrane Database Syst Rev, 2014; 4:CD000227. doi: 10.1002/14651858.CD000227.pub4.
139. Lanham SA, Cagampang FR, Oreffo ROC. The influence of a high fat diet on bone and soft tissue formation in Matrix Gla Protein knockout mice. Sci Rep, 2018; 8: 3635. doi.org/10.1038/s41598-018-21650-0.
140. Yao J, Guihard PJ, Blazquez-Medela AM et al. Matrix Gla protein regulates differentiation of endothelial cells derived from mouse embryonic stem cells. Angiogenesis, 2016; 19, 1–7. doi.org/10.1007/s10456-015-9484-3.
141. Dahlberg S, Schott U. Vitamin K and its Role in Diabetic Vascular Complications and Low-Grade Inflammation. J Diabetes Treat, 2018; 138. doi: 10.29011/2574-7568. 000038.
142. Dai L, Li L, Erlandsson H, et al. Functional vitamin K insufficiency, vascular calcification and mortality in advanced chronic kidney disease: A cohort study. PloS One, 2021; 16(2): e0247623. doi: 10.1371/journal.pone.0247623. eCollection 2021.
143. McCabe KM, Booth SL, Fu X, Ward E, Adams MA, Holden RM. . Vitamin K Metabolism in a Rat Model of Chronic Kidney Disease. Am J Nephrol, 2017; 45, 4–13. doi.org/10.1159/000451068.
144. Wang C, Zang H, Zhou D. Bone morphogenetic protein-2 exhibits therapeutic benefits for osteonecrosis of the femoral head through induction of cartilage and bone cells. Exp Ther Med, 2018; 15(5): 4298-4308. doi.org/10.3892/etm.2018.5941.
145. Herrmann M, Babler A, Moshkova I, et al. Lumenal calcification and microvasculopathy in fetuin-A-deficient mice lead to multiple organ morbidity. PloS One, 2020; 15(2):e0228503. doi:10.1371/journal.pone.0228503.
146. Lanham SA, Cagampang FR, Oreffo ROC. The influence of a high fat diet on bone and soft tissue formation in Matrix Gla Protein knockout mice. Sci Rep, 2018; 8: 3635. doi.org/10.1038/s41598-018-21650-0.
147. Viegas CS, Cavaco S, Neves PL, Ferreira A, João A, Williamson MK, Price PA, Cancela ML and Simes DC: Gla-rich protein is a novel vitamin K-dependent protein present in serum that accumulates at sites of pathological calcifications. Am J Pathol. 175:2288–2298. 2009. doi.org/10.1161/ATVBAHA.114.304823.
148. Surmann-Schmitt C, Dietz U, Kireva T, et al: Ucma, a novel secreted cartilage-specific protein with implications in osteogenesis. J Biol Chem, 2008; 11:7082–7893. doi: 2008. 10.1074/jbc.M702792200.
149. Viegas CS, Rafael MS, Enriquez JL, et al: Gla-rich protein (GRP) acts as a calcification inhibitor in the human cardiovascular system. Arterioscler Thromb Vasc Biol, 2015; 35:399–408. doi: 10.1161/ATVBAHA.114.304823.
150. Rafael MS, Cavaco S, Viegas CS, et al. Insights into the association of Gla-rich protein and osteoarthritis, novel splice variants and γ-carboxylation status. Mol Nutr Food Res. 58:1636–1646. 2014. doi:10.1002/mnfr.201300941.
151. Yamada S, Tokumoto M, Tsuruya K, et al. Fetuin-A decrease induced by a low-protein diet enhances vascular calcification in uremic rats with hyperphosphatemia. Am J Physiol Renal Physiol, 2015; 309(8):744-754. doi: 10.1152/ajprenal.00017.2015
152. Chen HY, Chiu YL, Hsu SP, Pai MF, Yang JY, Peng YS. Relationship between Fetuin A, Vascular Calcification and Fracture Risk in Dialysis Patients. PLoS One, 2016; 11(7): e0158789. doi: 10.1371/journal.pone.0158789.
153. Bourebaba L, Marycz K. Pathophysiological Implication of Fetuin-A Glycoprotein in the Development of Metabolic Disorders: A Concise Review. J Clin Med, 2019; 8(12): 2033. doi.org/10.3390/jcm8122033.
154. Kapustin AN, Chatrou ML, Drozdov I, et al. Vascular smooth muscle cell calcification is mediated by regulated exosome secretion. Circ Res, 2015; 116(8): 1312-23. doi: 10.1161/CIRCRESAHA.116.305012.
155. Rudloff S, Janot M, Rodriguez S et al. Fetuin-A is a HIF target that safeguards tissue integrity during hypoxic stress. Nat Commun, 2021; 12: 549. doi.org/10.1038/s41467-020-20832-7.
156. Cano-Megías M, Guisado-Vasco P, Bouarich H, et al. Coronary calcification as a predictor of cardiovascular mortality in advanced chronic kidney disease: a prospective long-term follow-up study. BMC Nephrol, 2019; 20: 188. doi.org/10.1186/s12882-019-1367-1.
157. Luna-Luna M Criales-Vera Medina-Leyte D, et al. Bone Morphogenetic Protein-2 and Osteopontin Gene Expression in Epicardial Adipose Tissue from Patients with Coronary Artery Disease Is Associated with the Presence of Calcified Atherosclerotic Plaques. Diabetes Metab Syndr Obes, 2020; 13: 1943-1951. doi: 10.2147/DMSO.S253632.
158. Cozzolino M, Galassi A, Ciceri P. Do we need new phosphate binders in dialysis? Clin Kidney J, 2021; 14(2): 474–475. doi.org/10.1093/ckj/sfaa246.
159. Bostom A, Pasch A Madsen T, et al. Serum Calcification Propensity and Fetuin-A: Biomarkers of Cardiovascular Disease in Kidney Transplant Recipients. Am J Nephrol, 2018; 48(1): 21-31. doi: 10.1159/000491025.
160. Uedono H, Mori K, Ochi A, et al. Effects of fetuin-A-containing calciprotein particles on posttranslational modifications of fetuin-A in HepG2 cells. Sci Rep 2021; 11: 7486. doi.org/10.1038/s41598-021-86881-0.
161. Cozzolino M, Ciceri P, Galassi A, et al. The Key Role of Phosphate on Vascular Calcification. Toxins (Basel), 2019; 11(4): 213. doi: 10.3390/toxins11040213.
162. Koeppert S, Ghallab A, Peglow S, et al. Live Imaging of Calciprotein Particle Clearance and Receptor Mediated Uptake: Role of Calciprotein Monomers. Front. Cell Dev Biol, 2021. doi.org/10.3389/fcell.2021.633925.
163. Bramania PK, Ruggajo P, Bramania R, et al. Prevalence of malnutrition inflammation complex syndrome among patients on maintenance haemodialysis at Muhimbili National Hospital in Tanzania: a cross-sectional study. BMC Nephrol, 2020; 21: 521. doi.org/10.1186/s12882-020-02171-3.
164. Kawate Y, Miyata H. The importance of nutritional intervention by dietitians for hyperphosphatemia in maintained hemodialysis patients. Ren Replace Ther, 2017; 3: 19. doi.org/10.1186/s41100-017-0095-x.