Essential role for proteinase-activated receptor-2 in arthritis
William R. Ferrell, … , Toru Kanke, Junichi Kawagoe
William R. Ferrell, … , Toru Kanke, Junichi Kawagoe
Published January 1, 2003
Citation Information: J Clin Invest. 2003;111(1):35-41. https://doi.org/10.1172/JCI16913.
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Essential role for proteinase-activated receptor-2 in arthritis

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.

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

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Chronic joint inflammation is inhibited by PAR-2 gene disruption and PAR...
Chronic joint inflammation is inhibited by PAR-2 gene disruption and PAR-2 is upregulated in inflamed tissues. (a) Comparison of the response to induction of adjuvant arthritis in PAR-2+/+ mice (filled triangles), PAR-2–/– mice (open circles), and heterozygous mice (filled squares). An acute (24–hour) phase is followed by a progressive increase in joint diameter that reached a plateau by about 14 days in all but the PAR-2–/– group, which did not develop a chronic response. Data are presented as mean ± SEM; n = 6–8. (b) X-gal staining of normal synovial tissue in a PAR-2–/– mouse shows a rich density of staining for β-galactosidase activity limited to endothelial cells along the length of the arteriole. (c) Two weeks after induction of adjuvant monoarthritis in the PAR-2–/– mouse there is marked discrete extravascular cellular staining (scale bar: 50 μm for both b and c). (d) X-gal staining of inflamed synovial tissue excised from the knee joints of four PAR-2–/– mice shows very dense staining compared with uninflamed tissues from the contralateral knees (scale bar: 5 mm).