title: Expression and proinflammatory role of proteinase-activated receptor 2 in rheumatoid synovium: ex vivo studies using a novel proteinase-activated receptor 2 antagonist.
abstract: OBJECTIVE
  Serine proteinases activate the G protein-coupled receptor, proteinase-activated receptor 2 (PAR-2), via cleavage and exposure of a tethered ligand. PAR-2 is known to exert proinflammatory actions in a murine model of arthritis, since PAR-2-deficient mice exhibit strikingly reduced articular inflammation. This study was undertaken to examine synovial PAR-2 expression and to determine the effect of a novel PAR-2 antagonist on synovial cytokine production, in order to investigate the hypothesis that PAR-2 plays a critical role in the pathogenesis of rheumatoid arthritis (RA).
  
  
  METHODS
  Using a monoclonal antibody to human PAR-2, expression in RA synovium and cultured synovial fibroblasts was characterized. The novel PAR-2 antagonist, ENMD-1068, was added to primary cultures of RA synovial tissue, from which spontaneous cytokine release was measured.
  
  
  RESULTS
  PAR-2 was substantially up-regulated in RA synovium compared with control synovial tissue from patients with osteoarthritis or seronegative inflammatory arthritis, neither of which exhibited significant PAR-2 expression. Importantly, spontaneous release of tumor necrosis factor alpha and interleukin-1beta from RA synovium was substantially inhibited by ENMD-1068, in a dose-dependent manner.
  
  
  CONCLUSIONS
  These findings identify PAR-2 as a novel upstream regulator of proinflammatory cytokine production in RA and indicate its potential as a novel therapeutic target in inflammatory arthritis.
authors.affiliation: University of Glasgow, Glasgow, UK.
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Kelso
authors.forename: William R
authors.initials: WR
authors.lastname: Ferrell
authors.forename: John C
authors.initials: JC
authors.lastname: Lockhart
authors.forename: Iona
authors.initials: I
authors.lastname: Elias-Jones
authors.forename: Todd
authors.initials: T
authors.lastname: Hembrough
authors.forename: Lynette
authors.initials: L
authors.lastname: Dunning
authors.forename: J Alastair
authors.initials: JA
authors.lastname: Gracie
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C518710:1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine; D053583:Interleukin-1beta; D010879:Piperazines; D044464:Receptor, PAR-2; D014409:Tumor Necrosis Factor-alpha