TRPV4-mediated calcium influx regulates terminal differentiation of Osteoclasts

Calcium signaling controls multiple cellular functions and is regulated by the release from internal stores and entry from extracellular fluid. In bone, osteoclast differentiation is induced by RANKL (receptor activator of NF-kappa B ligand)-evoked intracellular Ca2+ oscillations, which trigger nuclear factor-activated T cells (NFAT) c1-responsive gene transcription. However, the Ca2+ channels involved remain largely unidentified. Here we show that genetic ablation in mice of Trpv4, a Ca2+-permeable channel of the transient receptor potential (TRP) family, increases bone mass by impairing bone resorption. TRPV4 mediates basolateral Ca2+ influx specifically in large osteoclasts when Ca2+ oscillations decline. TRPV4-mediated Ca2+ influx hereby secures intracellular Ca2+ concentrations, ensures NFATc1-regulated gene transcription, and regulates the terminal differentiation and activity of osteoclasts. In conclusion, our data indicate that Ca2+ oscillations and TRPV4-mediated Ca2+ influx are sequentially required to sustain NFATc1-dependent gene expression throughout osteoclast differentiation, and we propose TRPV4 as a therapeutic target for bone diseases.