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Essential role for proteinase-activated receptor-2 in arthritis
William R. Ferrell, … , Toru Kanke, Junichi Kawagoe
William R. Ferrell, … , Toru Kanke, Junichi Kawagoe
Published January 1, 2003
Citation Information: J Clin Invest. 2003;111(1):35-41. https://doi.org/10.1172/JCI16913.
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Essential role for proteinase-activated receptor-2 in arthritis

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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.

Authors

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

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Figure 1

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Generation of PAR-2–deficient mice. (a) Structure of the PAR-2 targeting...
Generation of PAR-2–deficient mice. (a) Structure of the PAR-2 targeting vector (top), the wild-type PAR-2 allele (middle), and targeted allele (bottom) resulting from replacement recombination at the dashed crosses. The null allele was created by substitution of a reporter/selection cassette (dark and light blue boxes) for most of the exon 2 sequence (filled gray box). Non-exon–containing chromosomal and cloned genomic DNA sequence is shown by a thick black line and pBluescript plasmid sequence by a thin black line. Restriction enzyme sites ClaI (C), HindIII (H), KpnI (K), NotI (N), and SalI (S) are indicated by small arrows, and the sizes of relevant restriction fragments are shown by dotted lines. The targeted allele was identified by KpnI digestion and hybridization with the 5′ and 3′ flanking probe fragments (gray rectangles). (b) Southern blot analysis of KpnI-digested genomic DNA prepared from pups from an intercross mating of PAR-2 mice heterozygous (+/–) for the null allele, demonstrating the presence of viable mice homozygous for the null allele (–/–). (c) RT-PCR for β-actin (548 bp) and PAR-2 (380 bp) mRNA expression in articular (lane 1 and lane 3, respectively) and intestinal (positive control; lane 2 and lane 4, respectively) tissue from PAR-2+/+ mice. (d) High-power view (oil immersion, differential interference contrast) of a synovial arteriole from a PAR-2–/– mouse. (e) Synovial tissue from a PAR-2+/+ mouse. β-galactosidase activity absent in endothelial cells (arrow 1) from PAR-2+/+ mice compared with PAR-2–/– tissue. Erythrocytes (arrowheads) are clearly visible in the lumen as are surrounding smooth muscle cells (arrow 2). Scale bar: 10 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 5 patents
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