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lüll Functional characterization of TRPV4 as an osmotically sensitive ion channel in porcine articular chondrocytes Phan MN; Leddy HA; Votta BJ; Kumar S; Levy DS; Lipshutz DB; Lee SH; Liedtke W; Guilak FArthritis Rheum 2009[Oct]; 60 (10): 3028-37OBJECTIVE: Transient receptor potential vanilloid 4 (TRPV4) is a Ca(2+)-permeable channel that can be gated by tonicity (osmolarity) and mechanical stimuli. Chondrocytes, the cells in cartilage, respond to their osmotic and mechanical environments; however, the molecular basis of this signal transduction is not fully understood. This study was undertaken to demonstrate the presence and functionality of TRPV4 in chondrocytes. METHODS: TRPV4 protein expression was measured by immunolabeling and Western blotting. In response to TRPV4 agonist/antagonists, osmotic stress, and interleukin-1 (IL-1), changes in Ca(2+) signaling, cell volume, and prostaglandin E(2) (PGE(2)) production were measured in porcine chondrocytes using fluorescence microscopy, light microscopy, or immunoassay, respectively. RESULTS: TRPV4 was expressed abundantly at the RNA and protein levels. Exposure to 4alpha-phorbol 12,13-didecanoate (4alphaPDD), a TRPV4 activator, caused Ca(2+) signaling in chondrocytes, which was blocked by the selective TRPV4 antagonist, GSK205. Blocking TRPV4 diminished the chondrocytes' response to hypo-osmotic stress, reducing the fraction of Ca(2+) responsive cells, the regulatory volume decrease, and PGE(2) production. Ca(2+) signaling was inhibited by removal of extracellular Ca(2+) or depletion of intracellular stores. Specific activation of TRPV4 restored the defective regulatory volume decrease caused by IL-1. Chemical disruption of the primary cilium eliminated Ca(2+) signaling in response to either 4alphaPDD or hypo-osmotic stress. CONCLUSION: Our findings indicate that TRPV4 is present in articular chondrocytes, and chondrocyte response to hypo-osmotic stress is mediated by this channel, which involves both an extracellular Ca(2+) and intracellular Ca(2+) release. TRPV4 may also be involved in modulating the production or influence of proinflammatory molecules in response to osmotic stress.|Animals[MESH]|Calcium/metabolism[MESH]|Cartilage, Articular/*metabolism/pathology[MESH]|Cell Size[MESH]|Cells, Cultured[MESH]|Chondrocytes/*metabolism/pathology[MESH]|Dinoprostone/metabolism[MESH]|Interleukin-1/metabolism[MESH]|Models, Animal[MESH]|Osmosis/*physiology[MESH]|Phorbol Esters/pharmacology[MESH]|Signal Transduction/physiology[MESH]|Swine[MESH]|TRPV Cation Channels/antagonists & inhibitors/drug effects/*metabolism[MESH] |