Triggering of proteinase-activated receptor 4 leads to joint pain and inflammation in mice

Arthritis Rheum. 2009 Mar;60(3):728-37. doi: 10.1002/art.24300.


Objective: To investigate the role of proteinase-activated receptor 4 (PAR-4) in mediating joint inflammation and pain in mice.

Methods: Knee joint blood flow, edema, and pain sensitivity (as induced by thermal and mechanical stimuli) were assessed in C57BL/6 mice following intraarticular injection of either the selective PAR-4 agonist AYPGKF-NH(2) or the inactive control peptide YAPGKF-NH(2). The mechanism of action of AYPGKF-NH(2) was examined by pretreatment of each mouse with either the PAR-4 antagonist pepducin P4pal-10 or the bradykinin antagonist HOE 140. Finally, the role of PAR-4 in mediating joint inflammation was tested by pretreating mice with acutely inflamed knees with pepducin P4pal-10.

Results: PAR-4 activation caused a long-lasting increase in joint blood flow and edema formation, which was not seen following injection of the control peptide. The PAR-4-activating peptide was also found to be pronociceptive in the joint, where it enhanced sensitivity to a noxious thermal stimulus and caused mechanical allodynia and hyperalgesia. The proinflammatory and pronociceptive effects of AYPGKF-NH(2) could be inhibited by pepducin P4pal-10 and HOE 140. Finally, pepducin P4pal-10 ameliorated the clinical and physiologic signs of acute joint inflammation.

Conclusion: This study demonstrates that local activation of PAR-4 leads to proinflammatory changes in the knee joint that are dependent on the kallikrein-kinin system. We also show for the first time that PARs are involved in the modulation of joint pain, with PAR-4 being pronociceptive in this tissue. Thus, blockade of articular PAR-4 may be a useful means of controlling joint inflammation and pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Arthralgia / metabolism*
  • Arthritis / etiology*
  • Arthritis / metabolism*
  • Bradykinin / administration & dosage
  • Bradykinin / analogs & derivatives
  • Bradykinin / pharmacology
  • Bradykinin B2 Receptor Antagonists
  • Disease Models, Animal
  • Edema / metabolism
  • Injections, Intra-Articular
  • Mice
  • Mice, Inbred C57BL
  • Oligopeptides / administration & dosage
  • Oligopeptides / pharmacology
  • Receptor, Bradykinin B2 / metabolism
  • Receptors, Proteinase-Activated / agonists
  • Receptors, Proteinase-Activated / metabolism*
  • Regional Blood Flow / drug effects
  • Regional Blood Flow / physiology


  • AYPGKG-NH(2)
  • Anti-Inflammatory Agents, Non-Steroidal
  • Bradykinin B2 Receptor Antagonists
  • Oligopeptides
  • Receptor, Bradykinin B2
  • Receptors, Proteinase-Activated
  • palmitoyl-seryl-glycyl-arginyl-arginyl-tyrosyl-glycyl-histidyl-alanyl-leucyl-arginine
  • protease-activated receptor 4, mouse
  • icatibant
  • Bradykinin