[HTML][HTML] Essential role for proteinase-activated receptor-2 in arthritis

WR Ferrell, JC Lockhart, EB Kelso… - The Journal of …, 2003 - Am Soc Clin Investig
WR Ferrell, JC Lockhart, EB Kelso, L Dunning, R Plevin, SE Meek, AJH Smith, GD Hunter…
The Journal of clinical investigation, 2003Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation