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INFLAMMATION AND IMMUNOPHARMACOLOGY

Therapeutic Promise of Proteinase-Activated Receptor-2 Antagonism in Joint Inflammation

Center for Rheumatic Diseases, Royal Infirmary, Glasgow, Scotland, United Kingdom (E.B.K., W.R.F.); School of Engineering and Science, University of Paisley, Paisley, Scotland, United Kingdom (J.C.L., L.D., J.S.M.); EntreMed, Inc., Rockville, Maryland (T.H.); Department of Physiology and Pharmacology, University of Strathclyde, Scotland, United Kingdom (R.P.); Canadian Institutes of Health Research Proteinases and Inflammation Network, Departments of Pharmacology and Therapeutics and Medicine, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada (M.D.H.); and Abteilung Klinische Chemie und Klinische Biochemie, Klinikumsstandort Innenstadt der Ludwig-Maximilians-Universität, Munich, Germany (C.P.S.)

Biological therapies such as tumor necrosis factor- 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 PAR₂ 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 PAR₂ 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, N¹-3-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.

Address correspondence to: Prof. J. C. Lockhart, School of Engineering and Science, University of Paisley, Paisley, PA1 2BE, Scotland, UK. E-mail: john.lockhart{at}paisley.ac.uk

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