title: TNFalpha suppresses link protein and type II collagen expression in chondrocytes: Role of MEK1/2 and NF-kappaB signaling pathways.
abstract: Tumor necrosis factor alpha (TNFalpha) inhibits matrix synthesis by chondrocytes in rheumatoid arthritis and osteoarthritis; however, the underlying signaling pathways are poorly characterized. This study investigated the TNFalpha-activated pathways regulating expression of two key components of the cartilage matrix-link protein and type II collagen. In rat articular chondrocytes, TNFalpha decreased link protein and type II collagen mRNA to undetectable levels within 48 h. Levels of link protein mRNA recovered more readily than type II collagen mRNA following removal of the cytokine. TNFalpha-mediated reduction in mRNA of both matrix molecules occurred at the level of transcription and, for link protein, mRNA stability. Turnover of type II collagen and link protein mRNA was dependent on new protein synthesis. In both prechondrocytes and articular chondrocytes, TNFalpha induced concentration-dependent activation of MEK1/2 and NF-kappaB, but not p38 or JNK. Sustained activation of NF-kappaB was observed for up to 72 h following continuous or transient exposure to TNFalpha. Using pharmacological and molecular approaches, the MEK1/2 and NF-kappaB pathways were found to mediate inhibition of type II collagen and link protein gene expression by TNFalpha. Both prechondrocytes and articular chondrocytes are targets of TNFalpha. This study identifies pathways through which TNFalpha perturbs the synthesis and organization of articular cartilage matrix during inflammation.
authors.affiliation: CHIR Group in Skeletal Development and Remodeling, The University of Western Ontario, London, Ontario, Canada.
authors.forename: Cheryle A
authors.initials: CA
authors.lastname: Séguin
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Bernier
mesh_terms: D000818:Animals; D001168:Arthritis / Q000378:metabolism / Q000503:physiopathology; D002358:Cartilage, Articular / Q000378:metabolism / Q000503:physiopathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D024043:Collagen Type II / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D016326:Extracellular Matrix Proteins; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D011506:Proteins / Q000235:genetics*; D011509:Proteoglycans; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D000099249:Proteoglycan Link Protein
chemical_list: D024043:Collagen Type II; D016326:Extracellular Matrix Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D016328:NF-kappa B; D011506:Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000099249:Proteoglycan Link Protein