TY - JOUR AU - Ferrell, William R. AU - Lockhart, John C. AU - Kelso, Elizabeth B. AU - Dunning, Lynette AU - Plevin, Robin AU - Meek, Stephen E. AU - Smith, Andrew J.H. AU - Hunter, Gary D. AU - McLean, John S. AU - McGarry, Frances AU - Ramage, Robert AU - Jiang, Lu AU - Kanke, Toru AU - Kawagoe, Junichi T1 - Essential role for proteinase-activated receptor-2 in arthritis PY - 2003/01/01/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI16913 VL - 111 IS - 1 UR - https://doi.org/10.1172/JCI16913 SP - 35 EP - 41 PB - The American Society for Clinical Investigation ER -