title: Oncostatin M up-regulates tissue inhibitor of metalloproteinases-3 gene expression in articular chondrocytes via de novo transcription, protein synthesis, and tyrosine kinase- and mitogen-activated protein kinase-dependent mechanisms.
abstract: Cytokines and growth factors regulate physiologic and pathologic turn-over of cartilage extracellular matrix (ECM) by altering the balance between tissue inhibitors of metalloproteinases (TIMPs) and matrix metalloproteinases (MMPs). Oncostatin M (OSM) is a cytokine of the IL-6 family whose levels are increased in the serum and synovial fluids of patients with rheumatoid arthritis. We examined responsiveness of the TIMP-3 gene to OSM in articular chondrocytes and studied the regulatory and signaling mechanisms of this response. OSM induced TIMP-3 mRNA and protein expression in a dose- and time-dependent fashion. Concomitantly, stromelysin-1 and collagenase-1 RNA and activities were also induced. A cartilage matrix growth factor, TGF-beta, induced TIMP-3, but combined OSM and TGF-beta did not further increase the extent of induction, suggesting a lack of synergy between the two. OSM induction of TIMP-3 gene expression was dependent upon de novo protein synthesis and transcription. RNA decay time-courses suggested that the OSM-mediated increase of TIMP-3 RNA was not due to enhanced message stability and, along with inhibition by actinomycin-D, suggested a transcriptional control. The antiinflammatory glucocorticoid, dexamethasone, down-regulated this augmentation. Investigation of the signaling mechanisms revealed that protein tyrosine kinase inhibitors genistein and herbimycin A, as well as the specific mitogen-activated protein kinase (MAPK) kinase inhibitor PD98059, suppressed OSM-induced TIMP-3 message expression, suggesting the involvement of tyrosine kinases and mitogen-activated protein kinase cascades in the signaling of OSM leading to TIMP-3 RNA enhancement. Thus OSM can potentially alter the cartilage matrix metabolism by regulating genes like TIMP-3 and matrix metalloproteinases.
authors.affiliation: Louis-Charles Simard Research Center, Centre Hospitalier de l'Université de Montréal, Campus Notre-Dame and Department of Medicine, University of Montreal, Quebec, Canada.
authors.forename: W Q
authors.initials: WQ
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Zafarullah
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects*; D002417:Cattle; D002478:Cells, Cultured; D003609:Dactinomycin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D013268:Stimulation, Chemical; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D005419:Flavonoids; D019384:Nucleic Acid Synthesis Inhibitors; D010455:Peptides; D019717:Tissue Inhibitor of Metalloproteinase-3; D016212:Transforming Growth Factor beta; D053683:Oncostatin M; D003609:Dactinomycin; D003907:Dexamethasone; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one