Calcium signaling in osteoclast differentiation and bone resorption.

Calcium (Ca(2+)) signaling controls multiple cellular functions and is regulated by the release of Ca(2+) from internal stores and its entry from the extracellular fluid. Ca(2+) signals in osteoclasts are essential for diverse cellular functions including differentiation, bone resorption and gene transcription. Recent studies have highlighted the importance of intracellular Ca(2+) signaling for osteoclast differentiation. Receptor activator of NF-κB ligand (RANKL) signaling induces oscillatory changes in intracellular Ca(2+) concentrations, resulting in Ca(2+)/calcineurin-dependent dephosphorylation and activation of nuclear factor of activated T cells c1 (NFATc1), which translocates to the nucleus and induces osteoclast-specific gene transcription to allow differentiation of osteoclasts. Recently, some reports indicated that RANKL-induced Ca(2+) oscillation involved not only repetitive intracellular Ca(2+) release from inositol 1, 4, 5-triphosphate channels in Ca(2+) store sites, but also via store-operated Ca(2+) entry and Ca(2+) entry via transient receptor potential V channels during osteoclast differentiation. Ca(2+)-regulatory cytokines and elevation of extracellular Ca(2+) concentrations have been shown to increase intracellular Ca(2+) concentrations ([Ca(2+)](i)) in mature osteoclasts, regulating diverse cellular functions. RANKL-induced [Ca(2+)](i) increase has been reported to inhibit cell motility and the resorption of cytoskeletal structures in mature osteoclasts, resulting in suppression of bone-resorption activity. In conclusion, Ca(2+) signaling activates differentiation in osteoclast precursors but suppresses resorption in mature osteoclasts. This chapter focuses on the roles of long-term Ca(2+) oscillations in differentiation and of short-term Ca(2+) increase in osteoclastic bone resorption activity.