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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Figure 3

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Effects of PAR-2 agonists on synovial perfusion and joint swelling. (a) ...
Effects of PAR-2 agonists on synovial perfusion and joint swelling. (a) Laser Doppler image showing vasodilatation 1 minute after topical administration of 1 μg of the PAR-2 agonist SLIGRL-NH2 (SLIG) to PAR-2+/+ mice. (b) ASKH95 (1 μg) administered to PAR-2+/+ mice also elicits vasodilatation. (c) ASKH95 (1 μg) administered to PAR-2–/– mice is without effect. (d) The control peptide ASKH115 (1 μg) administered to PAR-2+/+ mice is without effect. (e) Histogram showing quantitative data for the vasodilator effect of SLIG in PAR-2+/+ mice (+/+ SLIG), ASKH95 in both PAR-2–/– mice (–/– 95) and wild-type mice (+/+ 95), and ASKH115 in wild-type mice (+/+ 115). Perfusion is measured in arbitrary “flux units” and color coded in the images, with dark blue being the lowest and dark red the highest. Data are presented as mean ± SEM. n = 5–7. *P < 0.01 compared with +/+ 95. (f) Intra-articular injection of 100 μg of SLIG in PAR-2+/+ mice (filled squares) elicits an increase in joint diameter that reaches a maximum within 4 hours but declines thereafter. The synthetic PAR-2 agonist ASKH95 (100 μg) produces joint swelling that reaches maximum by 24 hours and is sustained thereafter in PAR-2+/+ mice (filled circles), a response that differs significantly compared with the same dose of this peptide in PAR-2–/– mice (open circles) and control peptide ASKH115 in wild-type mice (filled triangles). Data are presented as mean ± SEM; n = 4–10.