Inducers and inhibitors of biomineralization: lessons from pathological calcification.
OBJECTIVE
Ectopic calcification is a common response to soft tissue injury and systemic mineral imbalance and can lead to devastating clinical consequences when present in joints, heart valves and blood vessels. We have hypothesized that mineralization of matrices in any tissue is normally controlled by a balance between procalcific and anticalcific regulatory proteins such that abnormal deposition of apatite is avoided. Alterations in this balance induced by injury, disease or genetic deficiency are postulated to induce ectopic mineral deposition. Over the past several years, we have developed in vitro and in vivo models of ectopic calcification to investigate potential inducers and inhibitors of this process.


RESULTS
Osteopontin, a secreted phosphoprotein, has emerged as a major inhibitor of ectopic mineralization. Osteopontin is a potent inhibitor of vascular cell calcification in vitro and mice lacking osteopontin are highly susceptible to ectopic calcification. Furthermore, osteopontin treatment of biomaterials protected against ectopic mineralization. Our studies indicate that in addition to inhibiting apatite crystal initiation and growth, osteopontin stimulates resorption of ectopic calcification via peripheral macrophages and giant cells. In contrast, inorganic phosphate has emerged as a major inducer of mineralization in these systems. Elevated inorganic phosphate (Pi) was shown to induce smooth muscle cell matrix calcification with morphological properties similar to those observed in calcified human valves and atherosclerotic plaques. Furthermore, mineralization induced by inorganic phosphate was dependent on the activity of the sodium-dependent phosphate cotransporter, Pit-1.


CONCLUSIONS
These studies implicate controlled, transcellular transport of Pi as a major requirement for matrix calcification.
Giachelli
C M
CM
Department of Bioengineering, University of Washington, Seattle, 98195, USA. ceci@u.washington.edu
D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism; D002113:Calcification, Physiologic / Q000502:physiology*; D002114:Calcinosis / Q000378:metabolism*; D006801:Humans; D053495:Osteopontin; D010710:Phosphates / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000378:metabolism*; D050611:Sodium-Phosphate Cotransporter Proteins, Type III / Q000378:metabolism
D010710:Phosphates; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D050611:Sodium-Phosphate Cotransporter Proteins, Type III; D053495:Osteopontin