Title | Essential role for proteinase-activated receptor-2 in arthritis. |
Publication Type | Journal Article |
Year of Publication | 2003 |
Authors | Ferrell WR, Lockhart JC, Kelso EB, Dunning L, Plevin R, Meek SE, Smith AG, Hunter GD, McLean JS, McGarry F, Ramage R, Jiang L, Kanke T, Kawagoe J |
Journal | J Clin Invest |
Volume | 111 |
Issue | 1 |
Pagination | 35-41 |
Date Published | 2003 Jan |
ISSN | 0021-9738 |
Keywords | Alleles, Animals, Arthritis, Cartilage, Endothelium, Exons, Femur, Genetic Vectors, Heterozygote, In Situ Hybridization, Inflammation, Mice, Models, Chemical, Models, Genetic, Oligopeptides, Peptides, Phenotype, Receptor, PAR-2, Receptors, Thrombin, Recombination, Genetic, Time Factors, Up-Regulation |
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. |
DOI | 10.1172/JCI16913 |
Alternate Journal | J. Clin. Invest. |
PubMed ID | 12511586 |
PubMed Central ID | PMC151840 |