Abstract

IntroductionThe 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.MethodsIL-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.ResultsIL-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.ConclusionsIL-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.

Highlights

  • 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

  • IL-17A serum levels were higher in patients with inflammatory arthritis compared with OA patients (24.3 ± 9.6 pg/ml vs. 12.32 ± 12.32 pg/ml)

  • In this study for the first time we have shown in human cells isolated from patients with inflammatory arthritis that IL-17A combined with oncostatin M (OSM) synergistically upregulates the expression of MMP1, matrix metalloproteinase (MMP)-2, MMP-9 and MMP-13 in both chondrocytes and RASFs

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Summary

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. Rheumatoid arthritis (RA) is a common autoimmune disease characterised by proliferation of synovial tissue (ST) and joint erosion [1]. Angiogenesis is an early, critical event enabling lymphocytes and macrophages to enter the joint cavity by active recruitment via the endothelium [2]. Cytokines and growth factors are required to stimulate cell survival, proliferation and extracellular matrix (ECM) degradation as part of this process [4]. Cartilage and bone degradation is characterised by a loss of ECM through activation of matrix metalloproteinases (MMPs) and decreased production of specific tissue inhibitors such as tissue inhibitor of metallo-

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