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Essential role for proteinase-activated receptor-2 in arthritis

Authors
  • William R. Ferrell
  • John C. Lockhart
  • Elizabeth B. Kelso
  • Lynette Dunning
  • Robin Plevin
  • Stephen E. Meek
  • Andrew J.H. Smith
  • Gary D. Hunter
  • John S. McLean
  • Frances McGarry
  • Robert Ramage
  • Lu Jiang
  • Toru Kanke
  • Junichi Kawagoe
Publisher
American Society for Clinical Investigation
Publication Date
Jan 01, 2003
Source
PMC
Keywords
Disciplines
  • Biology
  • Medicine
  • Pharmacology
License
Unknown

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.

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