Essential role for proteinase-activated receptor-2 in arthritis

J Clin Invest. 2003 Jan;111(1):35-41. doi: 10.1172/JCI16913.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*


  • 2-furoyl-leucyl-isoleucyl-glycyl-lysyl-valine
  • Oligopeptides
  • Peptides
  • Receptor, PAR-2
  • Receptors, Thrombin
  • phenylacetyl-leucyl-isoleucyl-glycyl-lysyl-valine