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Correlation of protease-activated receptor-2 expression and synovitis in rheumatoid and osteoarthritis

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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.

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Acknowledgments

This work was supported by grants from Arthritis Research UK (17728, 18901) and the Carnegie Trust. Expert technical support was provided by Elizabeth Burns and Marion Drew. We thank all the patients, the orthopaedic surgeons and the Bereavement Centre at the Sherwood Forest Hospitals NHS Foundation Trust for providing clinical material. We also thank Deborah Wilson, Roger Hill and the histopathology personnel at the King’s Mill Hospital for their help with participant recruitment and assessment, and the processing of tissue samples. We are grateful to AstraZeneca for financial support to assist the creation of the tissue repository used in this study.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. 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

    Alistair G. Tindell & Elizabeth B. Kelso

  2. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Room 407, Level 4, McGregor Building, Western Infirmary, Dumbarton Road, Glasgow, Scotland, G11 6NT, UK

    William R. Ferrell

  3. School of Science, University of the West of Scotland, Paisley, PA1 2BE, UK

    John C. Lockhart & Lynette Dunning

  4. Arthritis Research UK Pain Centre, Academic Rheumatology, University of Nottingham, Nottingham, NG5 1PB, UK

    David A. Walsh

  5. Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, B4/17, Glasgow Biomedical Research Centre, University Place, Glasgow, G12 8TA, UK

    Iain B. McInnes

Authors
  1. Alistair G. Tindell
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  2. Elizabeth B. Kelso
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  4. John C. Lockhart
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Correspondence to William R. Ferrell.

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Tindell, A.G., Kelso, E.B., Ferrell, W.R. et al. Correlation of protease-activated receptor-2 expression and synovitis in rheumatoid and osteoarthritis. Rheumatol Int 32, 3077–3086 (2012). https://doi.org/10.1007/s00296-011-2102-9

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  • DOI: https://doi.org/10.1007/s00296-011-2102-9

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