Essential role for proteinase-activated receptor-2 in arthritis

W.R. Ferrell, J.C. Lockhart, E.B. Kelso, L. Dunning, R.J. Plevin, S.E. Meek, A.J. Smith, G.D. Hunter, J.S. McLean, F. McGarry, R. Ramage, L. Jiang, T. Kanke, J. Kawagoe

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Abstract

Using physiological, pharmacological, and gene disruption approaches, we demonstrate that proteinase-activated receptor-2 (PAR-2) plays a pivotal role in mediating chronic inflammation. Using an adjuvant monoarthritis model of chronic inflammation, joint swelling was substantially inhibited in PAR-2-deficient mice, being reduced by more than fourfold compared with wild-type mice, with virtually no histological evidence of joint damage. Mice heterozygous for PAR-2 gene disruption showed an intermediate phenotype. PAR-2 expression, normally limited to endothelial cells in small arterioles, was substantially upregulated 2 weeks after induction of inflammation, both in synovium and in other periarticular tissues. PAR-2 agonists showed potent proinflammatory effects as intra-articular injection of ASKH95, a novel synthetic PAR-2 agonist, induced prolonged joint swelling and synovial hyperemia. Given the absence of the chronic inflammatory response in the PAR-2-deficient mice, our findings demonstrate a key role for PAR-2 in mediating chronic inflammation, thereby identifying a novel and important therapeutic target for the management of chronic inflammatory diseases such as rheumatoid arthritis.
Original languageEnglish
Pages (from-to)35-41
Number of pages6
JournalJournal of Clinical Investigation
Volume111
Issue number1
DOIs
Publication statusPublished - 2003

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