Essential role for proteinase-activated receptor-2 in arthritis.
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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.
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| Authors | William R Ferrell, John C Lockhart, Elizabeth B Kelso, Lynette Dunning, Robin Plevin, Stephen E Meek, Andrew J H Smith, Gary D Hunter, John S McLean, Frances McGarry, Robert Ramage, Lu Jiang, Toru Kanke, Junichi Kawagoe |
| Journal | The Journal of clinical investigation (J Clin Invest) Vol. 111 Issue 1 Pg. 35-41 (Jan 2003) ISSN: 0021-9738 [Print] United States |
| PMID | 12511586 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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