Regulation of bone turnover by calcium‐regulated calcium channels

Calcium plays multiple roles in osteoclast formation, survival, and activity. Intracellular calcium is determined both by the release of intracellular stores and the influx of extracellular calcium through a variety of calcium channels. Osteoclasts express several classes of calcium channels, including ryanodine receptors (RyRs), inositol‐1,4,5‐trisphosphate receptors (IP 3 Rs), and calcium release‐activated calcium channels (CRACs), which respond to depletion of intracellular stores. IP 3 R2 is expressed in osteoclast precursors and activated by cytokines that stimulate osteoclast differentiation. In mature osteoclasts, the IP 3 R1 isoform is highly expressed and is implicated in nitric oxide‐cGMP‐stimulated processes. RyR calcium channels may contribute to the release of intracellular calcium stores, while RyR2 in the plasma membrane may act to limit osteoclast activity based on extracellular calcium concentration. Orai, through regulation by endoplasmic reticular store‐sensing proteins, including Stim‐1, may also mediate calcium influx and act as a signal amplifier for calcium release by other calcium channels. Together, these receptors allow intracellular Ca 2+ signals to modulate bone turnover and, through calcium‐sensing functions, allow coupling of osteoclast activity to extracellular conditions and integrating additional cytokine and nitric oxide signals via transient intracellular calcium signals.