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

IntroductionTo examine IL-17A in patients, adjacent anti-tumour necrosis factor-alpha (TNF-alpha) therapy and the causatum of IL-17A on matrix turnover and cartilage degradation. Methods: IL-17A term was examined by ELISA and immunohistology in the rheumatoid arthritis (RA) joints. RA entire synovial tissue explant (RA ST), influential synovial fibroblasts (RASFC), human cartilage and chondrocyte cultures were stimulated with IL-17A +/- TNF-alpha and Oncostatin M (OSM). Matrix metalloproteinase (MMP) and tissue inhibitor (TIMP-1) were assessed by ELISA and zymography. Cartilage proteoglycan proceeds 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-alpha and OSM, IL-17A shifted the MMP:TIMP-1 ratio in favour of matrix degradation (all P<0.05). Cartilage proteoglycan depletion in response to IL-17A was mild, nevertheless in combination with TNF-alpha or OSM showed almost complete proteoglycan depletion. Serum IL-17A was detected in 28% of patients commencing biologic therapy. IL-17A con patients demonstrated reductions display therapy in serum MMP1/TIMP4, MMP3/TIMP1, MMP3/TIMP4 ratios and an exaggeration in CS846 (all P<0.05), no facund 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, remarkably in the presence of other cytokines, mimicking the joint environment. IL-17A levels are modulated in vivo, following anti-TNF therapy, and may cast changes in matrix turnover.

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