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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 4/2009

Open Access 01-08-2009 | Research article

Human rheumatoid arthritis tissue production of IL-17A drives matrix and cartilage degradation: synergy with tumour necrosis factor-α, Oncostatin M and response to biologic therapies

Authors: Ellen M Moran, Ronan Mullan, Jennifer McCormick, Mary Connolly, Owen Sullivan, Oliver FitzGerald, Barry Bresnihan, Douglas J Veale, Ursula Fearon

Published in: Arthritis Research & Therapy | Issue 4/2009

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Abstract

Introduction

The aim of this study was to examine IL-17A in patients, following anti-TNF-α therapy and the effect of IL-17A on matrix turnover and cartilage degradation.

Methods

IL-17A expression was examined by ELISA and immunohistology in the rheumatoid arthritis (RA) joints. RA whole synovial tissue explant (RA ST), primary synovial fibroblasts (RASFC), human cartilage and chondrocyte cultures were stimulated with IL-17A +/- TNF-α and Oncostatin M (OSM). Matrix metalloproteinase (MMP) and tissue inhibitor (TIMP-1) were assessed by ELISA and zymography. Cartilage proteoglycan release was assessed histologically by Safranin-O staining. Clinical parameters, IL-17A, MMP/TIMP were assessed in patients pre/post biologic therapy.

Results

IL-17A levels were higher in RA vs osteoarthritis (OA)/normal joints (P < 0.05). IL-17A up-regulated MMP-1, -2, -9, and -13 in RA ST, RASFC, cartilage and chondrocyte cultures (P < 0.05). In combination with TNF-α and OSM, IL-17A shifted the MMP:TIMP-1 ratio in favor of matrix degradation (all P < 0.05). Cartilage proteoglycan depletion in response to IL-17A was mild; however, in combination with TNF-α or OSM showed almost complete proteoglycan depletion. Serum IL-17A was detected in 28% of patients commencing biologic therapy. IL-17A negative patients demonstrated reductions post therapy in serum MMP1/TIMP4, MMP3/TIMP1 and MMP3/TIMP4 ratios and an increase in CS846 (all P < 0.05). No significant changes were observed in IL-17A positive patients.

Conclusions

IL-17A is produced locally in the inflamed RA joint. IL-17A promotes matrix turnover and cartilage destruction, especially in the presence of other cytokines, mimicking the joint environment. IL-17A levels are modulated in vivo, following anti-TNF therapy, and may reflect changes in matrix turnover.
Appendix
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Metadata
Title
Human rheumatoid arthritis tissue production of IL-17A drives matrix and cartilage degradation: synergy with tumour necrosis factor-α, Oncostatin M and response to biologic therapies
Authors
Ellen M Moran
Ronan Mullan
Jennifer McCormick
Mary Connolly
Owen Sullivan
Oliver FitzGerald
Barry Bresnihan
Douglas J Veale
Ursula Fearon
Publication date
01-08-2009
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 4/2009
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar2772

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