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lüll RANKL-induced TRPV2 expression regulates osteoclastogenesis via calcium oscillations Kajiya H; Okamoto F; Nemoto T; Kimachi K; Toh-Goto K; Nakayana S; Okabe KCell Calcium 2010[Nov]; 48 (5): 260-9The receptor activator of NFkappaB ligand (RANKL) induces Ca(2+) oscillations and activates the Nuclear Factor of Activated T cells 1 (NFATc1) during osteoclast differentiation (osteoclastogenesis). Ca(2+) oscillations are an important trigger signal for osteoclastogenesis, however the molecular basis of Ca(2+) permeable influx pathways serving Ca(2+) oscillations has not yet been identified. Using a DNA microarray, we found that Transient Receptor Potential Vanilloid channels 2 (TRPV2) are expressed significantly in RANKL-treated RAW264.7 cells (preosteoclasts) compared to untreated cells. Therefore, we further investigated the expression and functional role of TRPV2 on Ca(2+) oscillations and osteoclastogenesis. We found that RANKL dominantly up-regulates TRPV2 expression in preosteoclasts, and evokes spontaneous Ca(2+) oscillations and a transient inward cation current in a time-dependent manner. TRPV inhibitor ruthenium red and tetracycline-induced TRPV2 silencing significantly decreased both the frequency of Ca(2+) oscillations and the transient inward currents in RANKL-treated preosteoclasts. Silencing of store-operated Ca(2+) entry (SOCE) proteins similarly suppressed both RANKL-induced oscillations and currents in preosteoclasts. Furthermore, suppression of TRPV2 also reduced RANKL-induced NAFTc1 expression, its nuclear translocation, and osteoclastogenesis. In summary, Ca(2+) oscillations in preosteoclasts are triggered by RANKL-dependent TRPV2 and SOCE activation and intracellular Ca(2+) release. Subsequent activation of NFATc1 promotes osteoclastogenesis.|Animals[MESH]|Bone Resorption[MESH]|Calcium Channels/biosynthesis/deficiency/genetics/*physiology[MESH]|Calcium Signaling/drug effects/*physiology[MESH]|Cell Line[MESH]|Cells, Cultured[MESH]|Enzyme Inhibitors[MESH]|Gene Expression[MESH]|Gene Silencing[MESH]|Macrophages/drug effects/metabolism/physiology[MESH]|Membrane Glycoproteins/antagonists & inhibitors/deficiency/genetics[MESH]|Membrane Potentials/drug effects/physiology[MESH]|Mice[MESH]|NFATC Transcription Factors/metabolism[MESH]|ORAI1 Protein[MESH]|Oligonucleotide Array Sequence Analysis[MESH]|Osteoclasts/cytology/drug effects/*physiology[MESH]|RANK Ligand/antagonists & inhibitors/metabolism/*pharmacology[MESH]|Stromal Interaction Molecule 1[MESH]|TRPV Cation Channels/antagonists & inhibitors/biosynthesis/genetics/*physiology[MESH]|Type C Phospholipases/antagonists & inhibitors/metabolism[MESH] |