Ectopic calcification: new concepts in cellular regulation.
Ectopic calcification is a common response to soft tissue injury and systemic mineral imbalance, and can lead to devastating clinical consequences when present in heart valves or blood vessels. It is hypothesized that mesenchymal and inflammatory cells normally maintain the balance between procalcific and anti-calcific regulatory proteins in soft 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 calcification and found that: 1) elevated extracellular phosphate levels induce smooth muscle culture mineralization morphologically similar to that observed in calcified human valves and atherosclerotic plaques, 2) sodium-dependent phosphate cotransporter function is required for smooth muscle cell culture mineralization, 3) smooth muscle cell culture mineralization is associated with a dramatic loss of smooth muscle-specific gene expression and gain of osteoblast-like properties, including expression of osteoblast differentiation factor, Cbfa-1, and 4) osteopontin, a secreted phosphoprotein abundant in macrophages found in human calcified atherosclerotic and valvular lesions, is a potent inhibitor of ectopic calcification in vitro and in vivo. These studies suggest that both constitutively expressed (surveillance) and inducible (damage control) mineralization inhibitory molecules are produced by mesenchymal and inflammatory cells to control ectopic calcification.
Giachelli
C M
CM
Bioengineering Department, Box 351720, University of Washington, Seattle, WA 98195, USA. ceci@u.washington.edu
D001031:Apatites / Q000378:metabolism; D001161:Arteriosclerosis / Q000473:pathology*; D002114:Calcinosis / Q000473:pathology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D016326:Extracellular Matrix Proteins; D006349:Heart Valve Diseases / Q000473:pathology*; D006351:Heart Valves / Q000473:pathology; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D010006:Osteoblasts / Q000473:pathology; D053495:Osteopontin; D010710:Phosphates / Q000378:metabolism; D012795:Sialoglycoproteins / Q000378:metabolism; D000097568:Matrix Gla Protein
D001031:Apatites; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D053495:Osteopontin; D010710:Phosphates; D012795:Sialoglycoproteins; D000097568:Matrix Gla Protein; C506895:SPP1 protein, human