Ectopic calcification is a common response to soft tissue injury, and can lead to devastating clinical consequences when present in heart valves or blood vessels. It is hypothesized that vascular mesenchymal and inflammatory cells normally maintain the balance between pro- calcific and anti-calcific regulatory proteins in vascular tissues such that ectopic deposition of apatite is avoided. Alterations in this balance induced by injury or disease is postulated to induce ectopic apatite deposition. We have developed in vitro and in vivo models of ectopic vascular calcification and found that: 1) elevated extracellular phosphate levels induce smooth muscle cell (SMC) culture mineralization morphologically similar to that observed in calcified human valves and atherosclerotic plaques; 2) SMC culture mineralization is associated with a dramatic loss of SMC-specific gene expression and gain of osteoblast-like properties, including expression of CBFA-1; 3) osteopontin is abundant in macrophages associated with human and mouse calcified atherosclerotic and valvular lesions; and 4) osteopontin is a potent inhibitor of vascular cell calcification in vitro. This proposal will examine factors which mediate the pro-mineralizing phenotypic state of vascular mesenchymal cells, the role of intracellular phosphate signaling in controlling this phenotype, and the structure and function of osteopontin in inhibiting ectopic mineralization. In addition, mutant mice will be used to define the role of inflammatory cell types and major bone noncollagenous proteins in ectopic calcification of prosthetic valves. Finally, the role of osteopontin in regulating atherosclerotic calcification will be examined in ApoE X OPN double knockout mice. These studies will identify underlying mechanisms regulating ectopic mineralization, and identify novel strategies to prevent native and prosthetic vascular calcification.
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