The role of vitamin K in soft-tissue calcification

Abstract

Seventeen vitamin K-dependent proteins have been identified to date of which several are involved in regulating soft-tissue calcification. Osteocalcin, matrix Gla protein (MGP), and possibly Gla-rich protein are all inhibitors of soft-tissue calcification and need vitamin K-dependent carboxylation for activity. A common characteristic is their low molecular weight, and it has been postulated that their small size is essential for calcification inhibition within tissues. MGP is synthesized by vascular smooth muscle cells and is the most important inhibitor of arterial mineralization currently known. Remarkably, the extrahepatic Gla proteins mentioned are only partly carboxylated in the healthy adult population, suggesting vitamin K insufficiency. Because carboxylation of the most essential Gla proteins is localized in the liver and that of the less essential Gla proteins in the extrahepatic tissues, a transport system has evolved ensuring preferential distribution of dietary vitamin K to the liver when vitamin K is limiting. This is why the first signs of vitamin K insufficiency are seen as undercarboxylation of the extrahepatic Gla proteins. New conformation-specific assays for circulating uncarboxylated MGP were developed; an assay for desphospho-uncarboxylated matrix Gla protein and another assay for total uncarboxylated matrix Gla protein. Circulating desphospho-uncarboxylated matrix Gla protein was found to be predictive of cardiovascular risk and mortality, whereas circulating total uncarboxylated matrix Gla protein was associated with the extent of prevalent arterial calcification. Vitamin K intervention studies have shown that MGP carboxylation can be increased dose dependently, but thus far only 1 study with clinical endpoints has been completed. This study showed maintenance of vascular elasticity during a 3-y supplementation period, with a parallel 12% loss of elasticity in the placebo group. More studies, both in healthy subjects and in patients at risk of vascular calcification, are required before conclusions can be drawn.

Figures

Figure 1

Calcification induced by the warfarin + phylloquinone regimen. Calcifications (visualized by von Kossa staining) induced by feeding a DBA2 mouse warfarin (3 mg/g) and phylloquinone (1.5 mg/g) for 6 wk. A, liver; B, kidney; C, heart; D, aorta. The arrows indicate areas of calcifications. TA, tunica adventitia; EC, endocardium; H, hepatocytes; G, glomerulus; L, lumen; MC, myocardium; T, tubulus; TM, tunica media. (C. Vermeer et al., VitaK, Maastricht University, the Netherlands, unpublished results).

Figure 2

Carboxylated matrix Gla protein (cMGP) and uncarboxylated matrix Gla protein (ucMGP) in the arterial wall. Early and advanced lesions in the arterial wall were stained (red) for cMGP and ucMGP. A, cMGP in early lesion. B, cMGP in advanced lesion. C, ucMGP in early lesion. D, ucMGP in advanced lesion. TI, tunica intima; TM, tunica media. (C. Vermeer et al., VitaK, Maastricht University, the Netherlands, unpublished results).