Essential role for proteinase-activated receptor-2 in arthritis

William R Ferrell, John C Lockhart, Elizabeth B Kelso, Lynette Dunning, Robin Plevin, Stephen Meek, A. J. H Smith, G.D Hunter, John S McLean, Frances McGarry, Robert Ramage, Lu Jiang, Toru Kanke, Junichi Kawagoe

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)35-41
Number of pages7
JournalJournal of Clinical Investigation
Volume111
Issue number1
Publication statusPublished - Jan 2003

Keywords

  • Alleles
  • Animals
  • Arthritis/metabolism
  • Cartilage/injuries
  • Endothelium/metabolism
  • Exons
  • Femur/injuries
  • Genetic Vectors
  • Heterozygote
  • In Situ Hybridization
  • Inflammation
  • Mice
  • Models, Chemical
  • Models, Genetic
  • Oligopeptides/pharmacology
  • Peptides/pharmacology
  • Phenotype
  • Receptor, PAR-2
  • Receptors, Thrombin/agonists
  • Receptors, Thrombin/biosynthesis
  • Receptors, Thrombin/physiology
  • Recombination, Genetic
  • Time Factors
  • Up-Regulation

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