An environmental sensor, TRPV4 is a novel regulator of intracellular Ca2+ in human synoviocytes

The activation of a vanilloid type 4 transient receptor potential channel (TRPV4) has an obligatory role in regulation of intracellular CA(2+) (CA(2+)(i)) in several types of cells including vascular and sensory organs. In this study, we provide evidence that TRPV4 is a functional regulator of CA(2+)(i) in human synoviocytes. Although significant expression of TRPV4 in synoviocytes from patients with (RA) and without (CTR) rheumatoid arthritis was detected at mRNA and protein level, those in the human fibroblast-like synoviocyte line MH7A were rather lower. Consistently, the selective TRPV4 agonist 4alpha-phorbol 12,13-didecanoate (4alphaPDD) effectively elevated CA(2+)(i) in the RA and CTR cells, which was abolished by the removal of external CA(2+). Moreover, the elevation was inhibited by ruthenium red, a blocker of TRPVs. In MH7A cells transfected with human TRPV4 (MH7A-V4), 4alphaPDD elevated the CA(2+)(i) in a similar manner to those in the RA and CTR cells. Electrophysiological analysis also revealed that 4alphaPDD activated nonselective cationic currents in RA cells. Application of 227 mosM solution to the RA and MH7A-V4 cells elevated their CA(2+)(i), but this does not occur when it was applied to MH7A cells. Treatment of RA but not MH7A cells with 4alphaPDD for 24 h reduced their production of IL-8. These results suggest that an environmental sensor, TRPV4, is a novel regulator of intracellular CA(2+) in human synoviocytes.