Essential role for proteinase-activated receptor-2 in arthritis.
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.
Ferrell
William R
WR
Centre for Rheumatic Diseases, Royal Infirmary, University of Glasgow, Glasgow, United Kingdom. w.ferrell@bio.gla.ac.uk
Lockhart
John C
JC
Kelso
Elizabeth B
EB
Dunning
Lynette
L
Plevin
Robin
R
Meek
Stephen E
SE
Smith
Andrew J H
AJ
Hunter
Gary D
GD
McLean
John S
JS
McGarry
Frances
F
Ramage
Robert
R
Jiang
Lu
L
Kanke
Toru
T
Kawagoe
Junichi
J
D000483:Alleles; D000818:Animals; D001168:Arthritis / Q000378:metabolism*; D002356:Cartilage / Q000293:injuries; D004727:Endothelium / Q000378:metabolism; D005091:Exons; D005269:Femur / Q000293:injuries; D005822:Genetic Vectors; D006579:Heterozygote; D017403:In Situ Hybridization; D007249:Inflammation; D051379:Mice; D008956:Models, Chemical; D008957:Models, Genetic; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010641:Phenotype; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000819:agonists / Q000096:biosynthesis* / Q000502:physiology*; D011995:Recombination, Genetic; D013997:Time Factors; D015854:Up-Regulation
C471410:2-furoyl-leucyl-isoleucyl-glycyl-lysyl-valine; D009842:Oligopeptides; D010455:Peptides; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; C471409:phenylacetyl-leucyl-isoleucyl-glycyl-lysyl-valine