Dr. Hembrough owns stock and/or holds stock options in EntreMed Inc. Dr. McInness has received consulting fees and/or honoraria (less than $10,000 each) from Schering-Plough, AstraZeneca, and GlaxoSmithKline.
Expression and proinflammatory role of proteinase-activated receptor 2 in rheumatoid synovium: Ex vivo studies using a novel proteinase-activated receptor 2 antagonist
Article first published online: 27 FEB 2007
Copyright © 2007 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 56, Issue 3, pages 765–771, March 2007
How to Cite
Kelso, E. B., Ferrell, W. R., Lockhart, J. C., Elias-Jones, I., Hembrough, T., Dunning, L., Gracie, J. A. and McInnes, I. B. (2007), Expression and proinflammatory role of proteinase-activated receptor 2 in rheumatoid synovium: Ex vivo studies using a novel proteinase-activated receptor 2 antagonist. Arthritis & Rheumatism, 56: 765–771. doi: 10.1002/art.22423
- Issue published online: 27 FEB 2007
- Article first published online: 27 FEB 2007
- Manuscript Accepted: 28 NOV 2006
- Manuscript Received: 8 MAY 2006
- Arthritis Research Campaign, UK. Grant Number: 16421
- EntreMed Inc.
- Wellcome Trust
- University of Paisley
- Merck & Co.
Serine proteinases activate the G protein–coupled receptor, proteinase-activated receptor 2 (PAR-2), via cleavage and exposure of a tethered ligand. PAR-2 is known to exert proinflammatory actions in a murine model of arthritis, since PAR-2–deficient mice exhibit strikingly reduced articular inflammation. This study was undertaken to examine synovial PAR-2 expression and to determine the effect of a novel PAR-2 antagonist on synovial cytokine production, in order to investigate the hypothesis that PAR-2 plays a critical role in the pathogenesis of rheumatoid arthritis (RA).
Using a monoclonal antibody to human PAR-2, expression in RA synovium and cultured synovial fibroblasts was characterized. The novel PAR-2 antagonist, ENMD-1068, was added to primary cultures of RA synovial tissue, from which spontaneous cytokine release was measured.
PAR-2 was substantially up-regulated in RA synovium compared with control synovial tissue from patients with osteoarthritis or seronegative inflammatory arthritis, neither of which exhibited significant PAR-2 expression. Importantly, spontaneous release of tumor necrosis factor α and interleukin-1β from RA synovium was substantially inhibited by ENMD-1068, in a dose-dependent manner.
These findings identify PAR-2 as a novel upstream regulator of proinflammatory cytokine production in RA and indicate its potential as a novel therapeutic target in inflammatory arthritis.