Therapeutic promise of proteinase-activated receptor-2 antagonism in joint inflammation

Elizabeth B. Kelso, John C. Lockhart, Todd Hembrough, Lynette Dunning, Robin Plevin, Morley D. Hollenberg, Christian P. Sommerhoff, John S. McLean, William R. Ferrell

Research output: Contribution to journalArticlepeer-review

169 Citations (Scopus)


Biological therapies such as tumor necrosis factor-α inhibitors have advanced the treatment of rheumatoid arthritis, but one-third of patients do not respond to such therapy. Furthermore, these inhibitors are now usually administered in combination with conventional disease-modifying antirheumatic drugs, suggesting they have not achieved their early promise. This study investigates a novel therapeutic target, proteinase-activated receptor (PAR)-2, in joint inflammation. Intra-articular carrageenan/ kaolin (C/K) injection in mice resulted in joint swelling that was associated with synovial PAR 2 up-regulation. Inhibiting receptor up-regulation using small interfering RNA technology, as confirmed by immunoblotting, substantially reduced the inflammatory response in the joint. Serine proteinase-induced joint swelling was mediated primarily via PAR2 activation, since the response to exogenous application of trypsin and tryptase was absent in PAR 2 knockout mice. Furthermore, serine proteinase inhibitors were effective anti-inflammatory agents in this model. Disrupting proteolytic activation of PAR2 using antiserum (B5) directed to the receptor cleavage/activation site also attenuated C/K-induced inflammation, as did the similarly targeted PAR2 monoclonal antibody SAM-11. Finally, we report the activity of a novel small molecule PAR2 antagonist, N 1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine (ENMD-1068), that dose dependently attenuated joint inflammation. Our findings represent a major advance in collectively identifying PAR2 as a novel target for the future treatment of arthritis.

Original languageEnglish
Pages (from-to)1017-1024
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
Publication statusPublished - 1 Mar 2006


  • proteinase-activated receptor-2
  • joint inflammation
  • antiinflammatory agent
  • arthritis


Dive into the research topics of 'Therapeutic promise of proteinase-activated receptor-2 antagonism in joint inflammation'. Together they form a unique fingerprint.

Cite this