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

• Published in: Arthritis and rheumatism Vol. 60; no. 3; pp. 728 - 737
• Main Authors: McDougall, Jason J., Zhang, Chunfen, Cellars, Laurie, Joubert, Eva, Dixon, Chantelle M., Vergnolle, Nathalie
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.03.2009; Wiley
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Arthralgia - metabolism; Arthritis - etiology; Arthritis - metabolism; Biological and medical sciences; Bradykinin - administration & dosage; Bradykinin - analogs & derivatives; Bradykinin - pharmacology; Bradykinin B2 Receptor Antagonists; Disease Models, Animal; Diseases of the osteoarticular system; Edema - metabolism; Injections, Intra-Articular; Medical sciences; 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; Vertebrata; Mammalia; Pain; Mouse; Animal; Rodentia; Rheumatology; Inflammation; Joint
• ISSN: 0004-3591; 1529-0131
• 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‐NH2 or the inactive control peptide YAPGKF‐NH2. The mechanism of action of AYPGKF‐NH2 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‐NH2 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.