title: Role of transient receptor potential vanilloid 4 in rat joint inflammation.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: University of São Paulo, São Paulo, Brazil.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Denadai-Souza
authors.forename: Laurence
authors.initials: L
authors.lastname: Martin
authors.forename: Marco A Vieira
authors.initials: MA
authors.lastname: de Paula
authors.forename: Maria C Werneck
authors.initials: MC
authors.lastname: de Avellar
authors.forename: Marcelo N
authors.initials: MN
authors.lastname: Muscará
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vergnolle
authors.forename: Nicolas
authors.initials: N
authors.lastname: Cenac
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002351:Carrageenan; D015870:Gene Expression; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013704:Temporomandibular Joint / Q000187:drug effects / Q000378:metabolism*
chemical_list: D009842:Oligopeptides; D010703:Phorbol Esters; D044464:Receptor, PAR-2; D050916:TRPV Cation Channels; C486577:Trpv4 protein, rat; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide; C008876:phorbol-12,13-didecanoate; D002351:Carrageenan; D002118:Calcium