Role of transient receptor potential vanilloid 4 in rat joint inflammation

Objective To determine whether activation of transient receptor potential vanilloid 4 (TRPV‐4) induces inflammation in the rat temporomandibular joint (TMJ), and to assess the effects of TRPV‐4 agonists and proinflammatory mediators, such as a protease‐activated receptor 2 (PAR‐2) agonist, on TRPV‐4 responses. Methods Four hours after intraarticular injection of carrageenan into the rat joints, expression of TRPV‐4 and PAR‐2 in trigeminal ganglion (TG) neurons and in the TMJs were evaluated by real‐time reverse transcription–polymerase chain reaction and immunofluorescence, followed by confocal microscopy. The functionality of TRPV‐4 and its sensitization by a PAR‐2–activating peptide (PAR‐2–AP) were analyzed by measuring the intracellular Ca2+ concentration in TMJ fibroblast‐like synovial cells or TG neurons. Plasma extravasation, myeloperoxidase activity, and the head‐withdrawal threshold (index of mechanical allodynia) were evaluated after intraarticular injection of selective TRPV‐4 agonists, either injected alone or coinjected with PAR‐2–AP. Results In the rat TMJs, TRPV‐4 and PAR‐2 expression levels were up‐regulated after the induction of inflammation. Two TRPV‐4 agonists specifically activated calcium influx in TMJ fibroblast‐like synovial cells or TG neurons. In vivo, the agonists triggered dose‐dependent increases in plasma extravasation, myeloperoxidase activity, and mechanical allodynia. In synovial cells or TG neurons, pretreatment with PAR‐2–AP potentiated a TRPV‐4 agonist–induced increase in [Ca2+]i. In addition, TRPV‐4 agonist–induced inflammation was potentiated by PAR‐2–AP in vivo. Conclusion In this rat model, TRPV‐4 is expressed and functional in TG neurons and synovial cells, and activation of TRPV‐4 in vivo causes inflammation in the TMJ. Proinflammatory mediators, such as PAR‐2 agonists, sensitize the activity of TRPV‐4. These results identify TRPV‐4 as an important signal of inflammation in the joint.