title: Correlation of protease-activated receptor-2 expression and synovitis in rheumatoid and osteoarthritis.
abstract: Protease-activated receptor-2 (PAR-2) is known to be pro-inflammatory and increasing evidence points to an inflammatory component in osteoarthritis. This investigation examined the relationship between synovitis and PAR-2 expression, histological and immunohistochemical analysis being performed on synovial samples obtained from OA and RA patients, along with non-arthritic samples obtained by post mortem (PM). Samples were also analysed for PAR-4 expression, this receptor also having putative pro-inflammatory roles. Analysis involved comparison of inflammatory indices (synovial thickness and monocyte infiltration) with expression of PAR-2 and PAR-4. Synovial explants were also analysed for TNFα generation in the presence of a PAR-2 antagonist (ENMD-1068) or vehicle. OA synovia showed heterogeneity of inflammatory indicators, some samples overlapping with those from the RA cohort whilst others appeared similar to the PM cohort. PAR-2 expression, both in the lining layer and the interstitium, correlated strongly and significantly with synovial thickness (r = 0.91) and monocyte infiltration (r = 0.83), respectively (P < 0.001 in both cases), and this remains significant on individual cohort analysis. PAR-2 was co-localised to CD3 and CD68 cells in RA and OA synovium as well as fibroblasts derived from these synovia. PAR-4 was also expressed, but the relationship with inflammatory indicators was substantially weaker. Inflammatory indicators in OA synovia showed considerable variability, but correlated strongly with PAR-2 expression, suggesting PAR-2 upregulation in synovitis. Heterogeneity of inflammatory indicators was paralleled by wide variation in TNFα generation between samples. Secretion of this cytokine was dose-dependently inhibited by ENMD-1068, providing evidence of a functional role for PAR-2 in promoting synovitis.
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Room 405, Level 4, McGregor Building, Western Infirmary, Dumbarton Road, Glasgow, Scotland, G11 6NT, UK.
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Tindell
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Kelso
authors.forename: William R
authors.initials: WR
authors.lastname: Ferrell
authors.forename: John C
authors.initials: JC
authors.lastname: Lockhart
authors.forename: David A
authors.initials: DA
authors.lastname: Walsh
authors.forename: Lynette
authors.initials: L
authors.lastname: Dunning
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013585:Synovitis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C518710:1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine; D018836:Inflammation Mediators; D010879:Piperazines; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; D014409:Tumor Necrosis Factor-alpha; C112908:protease-activated receptor 4