Molecular regulation of cartilage and bone mineralization

Biomineralization is a cell-regulated process. Matrix vesicles, which are released from mineralization-competent cells, initiate the mineralization process. These particles contain channel-forming annexins II, V and VI, and an Na⁺/Pi symport system, which enable Ca²⁺ and inorganic phosphate (Pi) influx into the vesicles. Rapid Ca²⁺ and Pi influxes are required for the formation of the first mineral phase inside the vesicles. Furthermore, matrix vesicles contain plasma cell membrane glycoprotein 1 (PC-1), an enzyme which generates pyrophosphate (PPi). Extracellular PPi is also regulated by ank, a transmembrane protein that transports intracellular PPi to the extracellular milieu. PPi is an inhibitor of mineralization; however, matrix vesicle-associated alkaline phosphatase (TNAP) may degrade PPi and thus may not only provide Pi but more importantly remove an inhibitor of mineralization. The release of mineralization-competent matrix vesicles is regulated by annexin-mediated alteration of Ca²⁺ homeostasis, suggesting that targeting annexin functions might provide a novel therapeutic strategy to prevent pathological mineralization. Furthermore, the possible inhibitory function of other factors, such as matrix gla protein (MGP), in mineralization and cell differentiation is discussed.