Essential role for proteinase-activated receptor-2 in arthritis

W.R. Ferrell, J.C. Lockhart, E.B. Kelso, L. Dunning, R.J. Plevin, S.E. Meek, A.J. Smith, G.D. Hunter, J.S. McLean, F. McGarry, R. Ramage, L. Jiang, T. Kanke, J. Kawagoe

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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.
LanguageEnglish
Pages35-41
Number of pages6
JournalJournal of Clinical Investigation
Volume111
Issue number1
DOIs
Publication statusPublished - 2003

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PAR-2 Receptor
Arthritis
Inflammation
Joints
Intra-Articular Injections
Synovial Membrane
Hyperemia
Arterioles
Genes
Rheumatoid Arthritis
Chronic Disease
Endothelial Cells
Pharmacology
Phenotype

Cite this

Ferrell, W. R., Lockhart, J. C., Kelso, E. B., Dunning, L., Plevin, R. J., Meek, S. E., ... Kawagoe, J. (2003). Essential role for proteinase-activated receptor-2 in arthritis. Journal of Clinical Investigation, 111(1), 35-41. https://doi.org/10.1172/JCI200316913
Ferrell, W.R. ; Lockhart, J.C. ; Kelso, E.B. ; Dunning, L. ; Plevin, R.J. ; Meek, S.E. ; Smith, A.J. ; Hunter, G.D. ; McLean, J.S. ; McGarry, F. ; Ramage, R. ; Jiang, L. ; Kanke, T. ; Kawagoe, J. / Essential role for proteinase-activated receptor-2 in arthritis. In: Journal of Clinical Investigation. 2003 ; Vol. 111, No. 1. pp. 35-41.
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Ferrell, WR, Lockhart, JC, Kelso, EB, Dunning, L, Plevin, RJ, Meek, SE, Smith, AJ, Hunter, GD, McLean, JS, McGarry, F, Ramage, R, Jiang, L, Kanke, T & Kawagoe, J 2003, 'Essential role for proteinase-activated receptor-2 in arthritis' Journal of Clinical Investigation, vol. 111, no. 1, pp. 35-41. https://doi.org/10.1172/JCI200316913

Essential role for proteinase-activated receptor-2 in arthritis. / Ferrell, W.R.; Lockhart, J.C.; Kelso, E.B.; Dunning, L.; Plevin, R.J.; Meek, S.E.; Smith, A.J.; Hunter, G.D.; McLean, J.S.; McGarry, F.; Ramage, R.; Jiang, L.; Kanke, T.; Kawagoe, J.

In: Journal of Clinical Investigation, Vol. 111, No. 1, 2003, p. 35-41.

Research output: Contribution to journalArticle

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AU - Ferrell, W.R.

AU - Lockhart, J.C.

AU - Kelso, E.B.

AU - Dunning, L.

AU - Plevin, R.J.

AU - Meek, S.E.

AU - Smith, A.J.

AU - Hunter, G.D.

AU - McLean, J.S.

AU - McGarry, F.

AU - Ramage, R.

AU - Jiang, L.

AU - Kanke, T.

AU - Kawagoe, J.

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AB - 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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