Regulation of differentiated osteoclasts

Osteoclasts respond to many factors, including endocrines, cytokines, cell-cell interactions, and cell-matrix contacts. For mature osteoclasts, the first level of control occurs through signaling that follows binding to an appropriate substrate. Mononuclear and multinucleate osteoclasts are activated when cell surface integrins, notably but not exclusively alphavbeta3 integrins, bind to calcified matrices. The binding process results in actin ring formation and deployment of adhesive proteins into a ring shape such that a seal is formed. As this ring forms, components of the ruffled border assemble from diffuse distribution to form the resorption apparatus, which includes the vacuolar-ATPase, carbonic anhydrase, and other key molecules. This review focuses on the control of osteoclast activity, beginning with attachment and ruffled border assembly. Direct and indirect regulation by PTH/PTHrP, genomic and nongenomic effects of estrogen, and gene expression of ruffled border components, carbonic anhydrase, and vacuolar ATPase are reviewed. Finally, the need to understand complex signaling pathway interaction is discussed.