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.

Hdl Handle:
http://hdl.handle.net/10147/94198
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.
Authors:
Moran, Ellen M; Mullan, Ronan; McCormick, Jennifer; Connolly, Mary; Sullivan, Owen; Fitzgerald, Oliver; Bresnihan, Barry; Veale, Douglas J; Fearon, Ursula
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.
Citation:
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. 2009, 11 (4):R113 Arthritis Res. Ther.
Journal:
Arthritis research & therapy
Issue Date:
2009
URI:
http://hdl.handle.net/10147/94198
DOI:
10.1186/ar2772
PubMed ID:
19627579
Abstract:
INTRODUCTION: 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.
Language:
en
MeSH:
Antirheumatic Agents; Arthritis, Rheumatoid; Biological Therapy; Cartilage; Cells, Cultured; Drug Synergism; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix; Humans; Immunohistochemistry; Interleukin-17; Matrix Metalloproteinases; Oncostatin M; Organ Culture Techniques; Tissue Inhibitor of Metalloproteinase-1; Tumor Necrosis Factor-alpha
ISSN:
1478-6362

Full metadata record

DC FieldValue Language
dc.contributor.authorMoran, Ellen Men
dc.contributor.authorMullan, Ronanen
dc.contributor.authorMcCormick, Jenniferen
dc.contributor.authorConnolly, Maryen
dc.contributor.authorSullivan, Owenen
dc.contributor.authorFitzgerald, Oliveren
dc.contributor.authorBresnihan, Barryen
dc.contributor.authorVeale, Douglas Jen
dc.contributor.authorFearon, Ursulaen
dc.date.accessioned2010-03-12T15:35:29Z-
dc.date.available2010-03-12T15:35:29Z-
dc.date.issued2009-
dc.identifier.citationHuman 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. 2009, 11 (4):R113 Arthritis Res. Ther.en
dc.identifier.issn1478-6362-
dc.identifier.pmid19627579-
dc.identifier.doi10.1186/ar2772-
dc.identifier.urihttp://hdl.handle.net/10147/94198-
dc.description.abstractINTRODUCTION: 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.-
dc.language.isoenen
dc.subject.meshAntirheumatic Agents-
dc.subject.meshArthritis, Rheumatoid-
dc.subject.meshBiological Therapy-
dc.subject.meshCartilage-
dc.subject.meshCells, Cultured-
dc.subject.meshDrug Synergism-
dc.subject.meshEnzyme-Linked Immunosorbent Assay-
dc.subject.meshExtracellular Matrix-
dc.subject.meshHumans-
dc.subject.meshImmunohistochemistry-
dc.subject.meshInterleukin-17-
dc.subject.meshMatrix Metalloproteinases-
dc.subject.meshOncostatin M-
dc.subject.meshOrgan Culture Techniques-
dc.subject.meshTissue Inhibitor of Metalloproteinase-1-
dc.subject.meshTumor Necrosis Factor-alpha-
dc.titleHuman 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.en
dc.contributor.departmentDepartment 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.en
dc.identifier.journalArthritis research & therapyen
dc.description.provinceLeinster-
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