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

PARticipation in inflammation

“…Moreover, PAR-2 deficiency confers some protection against leukocyte rolling and margination that occurs upon exteriorization of the cremaster (14), hyperreactivity in allergic inflammation of the airway (15), allergic dermatitis (16), and hyperalgesia induced by formalin or mast cell degranulation (9). Ferrell et al (1) …”

“…In this issue of the JCI, Ferrell and colleagues report that mice lacking the proteinase-activated receptor-2 (PAR-2) were protected against a form of adjuvant-induced arthritis (1). Herein we discuss protease-activated receptors, their mechanism of activation, and the contexts in which they are thought to function.…”

Proteinase activated receptor (PAR) involvement in mediating arthritis pain and inflammation

“…In a model of chronic adjuvant-induced arthritis, PAR 2 knock-out mice develop significantly less joint swelling than wild-type mice and joint damage is almost non-existent [72]. Unfortunately, the authors did not look at pain hypersensitivity in these animals, though with reduced disease progression, it is likely that these PAR 2 deficient mice could also exhibit reduced joint hyperalgesia.…”

“…Unfortunately, the authors did not look at pain hypersensitivity in these animals, though with reduced disease progression, it is likely that these PAR 2 deficient mice could also exhibit reduced joint hyperalgesia. It was also noted that PAR 2 expression was up-regulated in inflamed arthritic tissues [72]. A role for PAR 2 in the pathogenesis of OA has also been proposed due to the observation that PAR 2 expression is increased in articular chondrocytes from OA patients compared to controls [73].…”

“…This is in contrast to the earlier work done by Ferrell et al and may be due to differences between the two strains of PAR 2 knock-out mice. In particular, Ferrell et al incorporated a b-galactosidase reporter gene into the disrupted PAR 2 gene, which could potentially have unforeseen side effects [72].…”