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

Abstract

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.

• Authors: Jason J McDougall, Chunfen Zhang, Laurie Cellars, Eva Joubert, Chantelle M Dixon, Nathalie Vergnolle
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 60 Issue 3 Pg. 728-37 (Mar 2009) ISSN: 0004-3591 [Print] United States
• PMID: 19248120 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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