title: TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts.
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.
authors.affiliation: Laboratory of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven, B-3000, Belgium.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Masuyama
authors.forename: Joris
authors.initials: J
authors.lastname: Vriens
authors.forename: Thomas
authors.initials: T
authors.lastname: Voets
authors.forename: Yuji
authors.initials: Y
authors.lastname: Karashima
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Owsianik
authors.forename: Rudi
authors.initials: R
authors.lastname: Vennekens
authors.forename: Liesbet
authors.initials: L
authors.lastname: Lieben
authors.forename: Sophie
authors.initials: S
authors.lastname: Torrekens
authors.forename: Karen
authors.initials: K
authors.lastname: Moermans
authors.forename: An
authors.initials: A
authors.lastname: Vanden Bosch
authors.forename: Roger
authors.initials: R
authors.lastname: Bouillon
authors.forename: Bernd
authors.initials: B
authors.lastname: Nilius
authors.forename: Geert
authors.initials: G
authors.lastname: Carmeliet