Oncostatin M in combination with tumor necrosis factor alpha induces cartilage damage and matrix metalloproteinase expression in vitro and in vivo.
OBJECTIVE
To determine the effects of the proinflammatory cytokine combination of oncostatin M (OSM) and tumor necrosis factor alpha (TNFalpha) on cartilage destruction in both in vitro and in vivo model systems.


METHODS
The release of collagen and proteoglycan was assessed in bovine cartilage explant cultures, while messenger RNA (mRNA) from bovine chondrocytes was analyzed by Northern blotting. Immunohistochemistry was performed on sections prepared from murine joints following injection of adenovirus vectors encoding murine OSM and/or murine TNFalpha.


RESULTS
The combination of OSM + TNFalpha induced significant collagen release from bovine cartilage, accompanied by high levels of active collagenolytic activity. Northern blot analysis indicated that this cytokine combination synergistically induced matrix metalloproteinase 1 (MMP-1), MMP-3, and MMP-13 mRNA. The in vivo data clearly indicated that OSM + TNFalpha overexpression increased MMP levels and decreased levels of tissue inhibitor of metalloproteinases 1 (TIMP-1). Specifically, OSM + TNFalpha induced marked synovial hyperplasia, inflammation, and cartilage and bone destruction with a concomitant increase in MMP expression in both cartilage and synovium and decreased TIMP-1 expression in the articular cartilage. These effects were markedly greater than those seen with either cytokine alone.


CONCLUSIONS
This study demonstrates that OSM + TNFalpha represents a potent proinflammatory cytokine combination that markedly induces MMP production in both cartilage and synovium, thus promoting joint destruction.
Hui
W
W
School of Clinical Medical Sciences, University of Newcastle, Newcastle-upon-Tyne, UK.
Rowan
A D
AD
Richards
C D
CD
Cawston
T E
TE
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002356:Cartilage / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D002417:Cattle; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000235:genetics* / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009666:Nose; D053683:Oncostatin M; D020370:Osteoarthritis, Knee / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D010455:Peptides / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000970:Antineoplastic Agents; C508351:OSM protein, human; C508352:Osm protein, mouse; D010455:Peptides; D011509:Proteoglycans; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D053683:Oncostatin M; D003094:Collagen; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1