Role of vitamin K and Gla proteins in the pathophysiology of osteoporosis and vascular calcification

Among the proteins known or suspected to be involved in bone and vascular biology are several members of the vitamin K-dependent or Gla protein family. This review focuses on the role of two of these: osteocalcin and matrix Gla protein. Osteocalcin metabolism has been implicated in the pathogenesis of osteoporosis through an unknown mechanism that may be linked to suboptimal vitamin K status resulting in its undercarboxylation and presumed dysfunction. Recent studies that have investigated this hypothesis are discussed, as are recent promising clinical studies of vitamin K supplementation in osteoporosis. A recently delineated function of matrix Gla protein is as a powerful inhibitor of calcification of arteries and cartilage. In the period covered by this review there have been several landmark studies using cell systems, whole animals and genetic techniques that have consolidated and extended our knowledge of the role of matrix Gla protein in the prevention of ectopic calcification.

[1]  M. Emi,et al.  Isolation and radiation hybrid mapping of dinucleotide repeat polymorphism at the human matrix Gla protein (MGP) locus , 1998, Journal of Human Genetics.

[2]  K. Watson.  Pathophysiology of Coronary Calcification , 2000, Journal of Cardiovascular Risk.

[3]  K. Hamulýak,et al.  Assay for human matrix gla protein in serum: potential applications in the cardiovascular field. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[4]  G. Stein,et al.  Regulated expression of the bone-specific osteocalcin gene by vitamins and hormones. , 1999, Vitamins and hormones.

[5]  J. Lian,et al.  Association of congenital deficiency of multiple vitamin K-dependent coagulation factors and the phenotype of the warfarin embryopathy: clues to the mechanism of teratogenicity of coumarin derivatives. , 1987, American journal of human genetics.

[6]  A. Lin,et al.  Vitamin K deficiency embryopathy: a phenocopy of the warfarin embryopathy due to a disorder of embryonic vitamin K metabolism. , 1997, American journal of medical genetics.

[7]  L. Klenerman,et al.  Electrochemical detection of depressed circulating levels of vitamin K1 in osteoporosis. , 1985, The Journal of clinical endocrinology and metabolism.

[8]  M. Shiraki,et al.  Vitamin K2 (Menatetrenone) Effectively Prevents Fractures and Sustains Lumbar Bone Mineral Density in Osteoporosis , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[9]  M Heer,et al.  Space flight is associated with rapid decreases of undercarboxylated osteocalcin and increases of markers of bone resorption without changes in their circadian variation: observations in two cosmonauts. , 2000, Clinical chemistry.

[10]  G. Colditz,et al.  Vitamin K intake and hip fractures in women: a prospective study. , 1999, The American journal of clinical nutrition.

[11]  G. Nelsestuen,et al.  Vitamin K-dependent proteins. , 2000, Vitamins and hormones.

[12]  H. Thijssen,et al.  Vitamin K status in human tissues: tissue-specific accumulation of phylloquinone and menaquinone-4 , 1996, British Journal of Nutrition.

[13]  J. Skepper,et al.  Calcification of human vascular cells in vitro is correlated with high levels of matrix Gla protein and low levels of osteopontin expression. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[14]  P. Weissberg,et al.  Expression of mineralisation-regulating proteins in association with human vascular calcification , 2000, Zeitschrift für Kardiologie.

[15]  M. Shearer.  The roles of vitamins D and K in bone health and osteoporosis prevention , 1997, Proceedings of the Nutrition Society.

[16]  S. Booth,et al.  Warfarin use and fracture risk. , 2009 .

[17]  K. Tsaioun.  Vitamin K-dependent proteins in the developing and aging nervous system. , 2009, Nutrition reviews.

[18]  P. Munroe,et al.  Mutations in the gene encoding the human matrix Gla protein cause Keutel syndrome , 1999, Nature Genetics.

[19]  P. Weissberg,et al.  The role of Gla proteins in vascular calcification. , 1998, Critical reviews in eukaryotic gene expression.

[20]  K. Boström.  Cell differentiation in vascular calcification , 2000, Zeitschrift für Kardiologie.

[21]  S. Kawai,et al.  Menatetrenone plus alfacalcidol treatment for bone problems in eight children with skeletal unloading , 2000, Journal of Bone and Mineral Metabolism.

[22]  M. Urist,et al.  Matrix Gla protein, a new gamma-carboxyglutamic acid-containing protein which is associated with the organic matrix of bone. , 1983, Biochemical and biophysical research communications.

[23]  M. Kimura,et al.  Short-Term Effect of Vitamin K Administration on Prednisolone-Induced Loss of Bone Mineral Density in Patients with Chronic Glomerulonephritis , 2000, Calcified Tissue International.

[24]  D. Danks,et al.  Chondrodysplasia punctata-23 cases of a mild and relatively common variety. , 1976, The Journal of pediatrics.

[25]  C. Kanthou,et al.  The anticoagulant factor, protein S, is produced by cultured human vascular smooth muscle cells and its expression is up-regulated by thrombin. , 2000, Blood.

[26]  D. Kiel,et al.  Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women. , 2000, The American journal of clinical nutrition.

[27]  P. Weissberg,et al.  Medial localization of mineralization-regulating proteins in association with Mönckeberg's sclerosis: evidence for smooth muscle cell-mediated vascular calcification. , 1999, Circulation.

[28]  P. Price,et al.  Warfarin causes rapid calcification of the elastic lamellae in rat arteries and heart valves. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[29]  W. Jee,et al.  Excessive mineralization with growth plate closure in rats on chronic warfarin treatment. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[30]  R. Behringer,et al.  Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein , 1997, Nature.

[31]  P. Weissberg,et al.  Vascular calcification: new insights into an old problem , 1998, The Journal of pathology.

[32]  L. Fitzpatrick,et al.  Vascular calcification. , 1999, Current opinion in nephrology and hypertension.

[33]  M. McKee,et al.  Trends in Molecular Medicine: Molecular determinants of arterial calcification , 1998 .

[34]  P. Price,et al.  Warfarin-induced artery calcification is accelerated by growth and vitamin D. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[35]  M. McKee,et al.  Molecular determinants of arterial calcification. , 1998, Annals of medicine.

[36]  M. Frye,et al.  Osteoporosis and calcification of the aorta. , 1992, Bone and mineral.

[37]  D. Sane,et al.  Matrix Gla Protein Synthesis and Gamma-carboxylation in the Aortic Vessel Wall and Proliferating Vascular Smooth Muscle Cells , 1999, Thrombosis and Haemostasis.