Role of transient receptor potential vanilloid 4 in rat joint inflammation

Arthritis Rheum. 2012 Jun;64(6):1848-58. doi: 10.1002/art.34345. Epub 2011 Dec 19.


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 Ca(2+) 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 [Ca(2+) ](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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Carrageenan
  • Gene Expression
  • Hyperalgesia / genetics
  • Hyperalgesia / metabolism
  • Inflammation / chemically induced
  • Inflammation / metabolism*
  • Male
  • Neurons / drug effects
  • Neurons / metabolism*
  • Oligopeptides / pharmacology
  • Phorbol Esters / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, PAR-2 / agonists
  • Receptor, PAR-2 / genetics
  • Receptor, PAR-2 / metabolism
  • Synovial Membrane / drug effects
  • Synovial Membrane / metabolism*
  • TRPV Cation Channels / agonists
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*
  • Temporomandibular Joint / drug effects
  • Temporomandibular Joint / metabolism*


  • Oligopeptides
  • Phorbol Esters
  • Receptor, PAR-2
  • TRPV Cation Channels
  • Trpv4 protein, rat
  • seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide
  • phorbol-12,13-didecanoate
  • Carrageenan
  • Calcium