title: 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.
abstract: BACKGROUND
  The aim of this study was to examine IL-17A in patients, following anti-TNF-alpha 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-alpha 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-alpha 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-alpha 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.
authors.affiliation: Department of Rheumatology, St, Vincent's University Hospital, Dublin Academic Healthcare and The Conway Institute of Biomolecular and Biomedical Research, Elm Park, Dublin 4, Ireland. el.moran@ucd.ie.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Moran
authors.forename: Ronan
authors.initials: R
authors.lastname: Mullan
authors.forename: Jennifer
authors.initials: J
authors.lastname: McCormick
authors.forename: Mary
authors.initials: M
authors.lastname: Connolly
authors.forename: Owen
authors.initials: O
authors.lastname: Sullivan
authors.forename: Oliver
authors.initials: O
authors.lastname: Fitzgerald
authors.forename: Barry
authors.initials: B
authors.lastname: Bresnihan
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Veale
authors.forename: Ursula
authors.initials: U
authors.lastname: Fearon
mesh_terms: D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism*; D001691:Biological Therapy; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000187:drug effects / Q000378:metabolism; D053683:Oncostatin M / Q000494:pharmacology*; D009924:Organ Culture Techniques; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D018501:Antirheumatic Agents; D020381:Interleukin-17; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D053683:Oncostatin M; D020782:Matrix Metalloproteinases