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. 2008 Sep;8(3):257-65.
doi: 10.1016/j.cmet.2008.08.002.

TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts

Ritsuko Masuyama  1 , Joris Vriens, Thomas Voets, Yuji Karashima, Grzegorz Owsianik, Rudi Vennekens, Liesbet Lieben, Sophie Torrekens, Karen Moermans, An Vanden Bosch, Roger Bouillon, Bernd Nilius, Geert Carmeliet
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Free article

TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts

Ritsuko Masuyama et al. Cell Metab. 2008 Sep.
Free article

Abstract

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-kappaB ligand)-evoked intracellular Ca(2+) oscillations, which trigger nuclear factor-activated T cells (NFAT) c1-responsive gene transcription. However, the Ca(2+) channels involved remain largely unidentified. Here we show that genetic ablation in mice of Trpv4, a Ca(2+)-permeable channel of the transient receptor potential (TRP) family, increases bone mass by impairing bone resorption. TRPV4 mediates basolateral Ca(2+) influx specifically in large osteoclasts when Ca(2+) oscillations decline. TRPV4-mediated Ca(2+) influx hereby secures intracellular Ca(2+) concentrations, ensures NFATc1-regulated gene transcription, and regulates the terminal differentiation and activity of osteoclasts. In conclusion, our data indicate that Ca(2+) oscillations and TRPV4-mediated Ca(2+) influx are sequentially required to sustain NFATc1-dependent gene expression throughout osteoclast differentiation, and we propose TRPV4 as a therapeutic target for bone diseases.

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