Arterial Calci ¢ cation : A Review of Mechanisms , AnimalModels , andthe Prospects forTherapy

The causes of arterial calci®cation are beginning to be elucidated. Macrophages, mast cells, and smooth muscle cells are the primary cells implicated in this process. The roles of a variety of bone-related proteins including bone morphogenetic protein-2 (BMP-2), matrix Gla protein (MGP), osteoprotegerin (OPG), osteopontin, and osteonectin in regulating arterial calci®cation are reviewed. Animals lacking MGP, OPG, smad6, carbonic anhydrase isoenzyme II, ®brillin-1, and klotho gene product develop varying extents of arterial calci®cation. Hyperlipidemia, vitamin D, nicotine, and warfarin, alone or in various combinations, produce arterial calci®cation in animal models. MGP has recently been discovered to be an inhibitor of bone morphogenetic protein-2, the principal osteogenic growth factor. Many of the forces that induce arterial calci®cation may act by disrupting the essential post-translational modi®cation of MGP, allowing BMP-2 to induce mineralization. MGP requires gamma-carboxylation before it is functional, and this process uses vitamin K as an essential cofactor. Vitamin K de®ciency, drugs that act as vitamin K antagonists, and oxidant stress are forces that could prevent the formation of GLA residues on MGP. The potential role of arterial apoptosis in calci®cation is discussed. Potential therapeutic options to limit the rate of arterial calci®cation are summarized. ß 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 4, 274±301, 2001