TNFα suppresses link protein and type II collagen expression in chondrocytes:: Role of MEK1/2 and NF-κB signaling pathways

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 11 collagen. In rat articular chondrocytes, TNFalpha decreased link protein and type 11 collagen mRNA to undetectable levels within 48 h. Levels of link protein mRNA recovered more readily than type 11 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 11 collagen and link protein m RNA was dependent on new protein synthesis. In both prechondrocytes and articular chondrocytes, TNFa 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 11 collagen and link protein gene expression by TNFalpha. Both prechondrocytes and articular chondrocytes are targets of TNFalpha This study identifies pathways through which TNFa perturbs the synthesis and organization of articular cartilage matrix during inflammation. (C) 2003 Wiley-Liss, Inc.