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

Ferrell, W.R. and Lockhart, J.C. and Plevin, R.J. (2008) Protease-activated receptor-2 (PAR-2): a potential new target in arthritis. Drugs of the Future, 33 (3). pp. 241-248. ISSN 0377-8282 (http://dx.doi.org/10.1358/dof.2008.033.03.1184546)

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Abstract

Protease-activated receptors (PARs) are a novel family of seven-transmembrane G-protein-coupled receptors. The unique feature of this family is that activation is initiated by cleavage of the N-terminus by serine 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. Synovial expression of this receptor is greatly upregulated in murine models of arthritis, and both acute and chronic experimental monoarthritis are 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 upregulated in synovial tissues from patients with rheumatoid arthritis (RA), and appears to be an upstream regulator of proinflammatory cytokine generation, including tumor necrosis factor alpha (TNF-alpha). 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.

ORCID iDs

Ferrell, W.R., Lockhart, J.C. and Plevin, R.J. ORCID logoORCID: https://orcid.org/0000-0002-7849-1220;
CORE (COnnecting REpositories)