Figure 2 |.

Proposed mechanistic links between metabolic bone disease, atherosclerosis, and vascular calcification. Passive, vessel-mediated calcification in an advanced atherosclerotic lesion may involve apoptosis and/or necrosis of cells in core regions of plaques, which results in the development of an area rich in acidic phospholipids complexed with Ca²⁺, and/or an elevated local CaPi ion product. CaPi precipitation could then lead to the formation and growth of amorphous CaPi and eventually to hydroxyapatite crystals in the vessel. The loss of local inhibitors of mineralization could remove the block to local crystal formation and growth and allow mineralization to progress. The presence of plaque mineral crystals could then facilitate a process whereby local cells dedifferentiate and/or become quiescent and assume a phenotype consistent with the bone remodeling process (that is, osteoblasts and/or osteoclasts), or lead to recruitment of pluripotent circulating cells (osteoprogenitor or chondroprogenitor cells) to the site. More active models of vascular calcification involve increased activity of local enzymes (phosphatases), which catalyze amorphous CaPi precipitation and crystal formation through increases in free inorganic phosphate generated through hydrolysis of organic phosphates. Active programmed models in which resident vascular cells independently assume a phenotype consistent with mineralizing cells (chondrocytes or osteoblasts) and initiate the initial precipitation of CaPi have also been suggested. This phenotypic change might occur, in part, in response to oxidized lipids, hyperglycemia, or inflammation in the vessel wall. Postulated mechanisms linking bone loss directly to mineralization in the artery include the release of Ca²⁺ and Pi from bone, perhaps in the form of CaPi complexes, which then localize to atherosclerosis-prone vascular sites where they form a nidus for future mineralization or lead to locally elevated Ca²⁺ and/or Pi levels. These increased levels would then promote spontaneous CaPi precipitation or growth of arterial CaPi precipitates or hydroxyapatite. Abbreviations: CaPi, calcium phosphate; MGP, matrix Gla protein; PPi, pyrophosphate; VSMC, vascular smooth muscle cell.