Calcium signaling in osteoclast differentiation and bone resorption

Abstract

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. © 2012 Springer Science+Business Media B.V.