Involvement of Transient Receptor Potential Vanilloid Channel 2 in the Induction of Lubricin and Suppression of Ectopic Endochondral Ossification in Mouse Articular Cartilage

Objective: Transient receptor potential vanilloid channel 2 (TRPV2) is a Ca²⁺-permeable channel and plays a role in mediating intracellular Ca²⁺ current via mechanical stimuli. This study was undertaken to examine the expression and role of TRPV2 in adult articular cartilage and the development of osteoarthritis (OA). Methods: We examined TRPV2 expression in mouse and human articular cartilage. We analyzed the development of OA in Col2a1-Cre^ERt2;Trpv2^fl/fl mice and Trpv2^fl/fl littermates in the resection of the medial meniscus and medial collateral ligament model (n = 5 each), the destabilization of the medial meniscus model (n = 5 each), and the aging mouse model (n = 8–9 each). We examined marker protein expression in these joints, Ca²⁺ influx by mechanical stimuli, and downstream pathways in vitro. Results: TRPV2 was expressed in mouse and human articular cartilage and ectopic ossification lesions. In all mouse models of OA examined, Col2a1-Cre^ERt2;Trpv2^fl/fl mice were observed to have enhanced degradation of articular cartilage accompanied by decreased expression of lubricin/Prg 4, and marked formation of periarticular ectopic ossification. Mechanical stress–induced Ca²⁺ influx was decreased by Trpv2 knockout (KO). Prg4 induction by fluid-flow shear stress was diminished in Trpv2-KO mouse chondrocytes, and this was mediated by the Ca²⁺/calmodulin-dependent protein kinase kinase-cyclic AMP response element binding protein axis. Hypertrophic differentiation was enhanced in Trpv2-KO mouse chondrocytes. Increased activity of calcineurin and nuclear translocation of nuclear factor in activated T cells 1 induced by fluid-flow shear stress or TRP agonist treatment was reversed by Trpv2 knockout. Conclusion: Our findings demonstrate regulation of articular cartilage by TRPV2 through Prg4 induction and suppression of ectopic ossification.