Essential role for proteinase-activated receptor-2 in arthritis

Ferrell, W.R. et al. (2003) Essential role for proteinase-activated receptor-2 in arthritis. Journal of Clinical Investigation, 111, pp. 35-41. (doi: 10.1172/JCI200316913)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kelso, Mrs Elizabeth and Ferrell, Professor William
• Authors: Ferrell, W.R., Lockhart, J.C., Kelso, E.B., Dunning, L., Plevin, R., Meek, S.E., Smith, A.J.H., Hunter, G.D., McLean, J.S., McGarry, F., Ramage, R., Jiang, L., Kanke, T., and Kawagoe, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Dental School; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Clinical Investigation
• Publisher: Americal Society for Clinical Investigation
• ISSN: 0021-9738