Expression and proinflammatory role of proteinase-activated receptor 2 in rheumatoid synovium: ex vivo studies using a novel proteinase-activated receptor 2 antagonist

Arthritis Rheum. 2007 Mar;56(3):765-71. doi: 10.1002/art.22423.


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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation
  • Humans
  • Interleukin-1beta / metabolism
  • Middle Aged
  • Piperazines / pharmacology
  • Receptor, PAR-2 / antagonists & inhibitors
  • Receptor, PAR-2 / genetics
  • Receptor, PAR-2 / metabolism*
  • Synovial Membrane / drug effects
  • Synovial Membrane / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism


  • 1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine
  • Interleukin-1beta
  • Piperazines
  • Receptor, PAR-2
  • Tumor Necrosis Factor-alpha