Protease-activated receptor-2 (PAR-2): a potential new target in arthritis

摘要

Protease-activated receptors (PARs) are a novel family of seven-transmembrane G-prote1n-coup!ed receptors: The unique feature of this family is that activation is initiated by cleavage of the N-terrninus by ser-ine or other proteases, thereby unmasking a tethered ligand that then interacts with the receptor, leading to activation. PARs have been described in the context of inflammation, and recent evidence indicates a particular role for the second member of this family, PAR-2, in arthritis. Synovia! expression of this receptor is greatly upreguiated in murine models of arthritis, and both acute and chronic; experimental monoarthritisare substantially attenuated in Par2 knockout mice, suggesting a key role for PAR-2 in inflammatory, joint disease. These findings translate to inflammatory disease in humans, since PAR-2 expression is upreguiated in synovial tissues from patients with rheumatoid arthritis (RA}, and appears to be an upstream regulator of proinflammatory cytokine generation, including tumornecrosis factor a (TNF-a). These findings identify PAR-2 as a new therapeutic target in the management of RA, and the challenge is now to develop potent and selective agents to prevent activation of this receptor.