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

✍ Scribed by Cheryle A. Séguin; Suzanne M. Bernier

• Publisher: John Wiley and Sons
• Year: 2003
• Tongue: English
• Weight: 413 KB
• Volume: 197
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.10371

✦ Synopsis

Abstract

Tumor necrosis factor α (TNFα) inhibits matrix synthesis by chondrocytes in rheumatoid arthritis and osteoarthritis; however, the underlying signaling pathways are poorly characterized. This study investigated the TNFα‐activated pathways regulating expression of two key components of the cartilage matrix—link protein and type II collagen. In rat articular chondrocytes, TNFα 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. TNFα‐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, TNFα induced concentration‐dependent activation of MEK1/2 and NF‐κB, but not p38 or JNK. Sustained activation of NF‐κB was observed for up to 72 h following continuous or transient exposure to TNFα. Using pharmacological and molecular approaches, the MEK1/2 and NF‐κB pathways were found to mediate inhibition of type II collagen and link protein gene expression by TNFα. Both prechondrocytes and articular chondrocytes are targets of TNFα. This study identifies pathways through which TNFα perturbs the synthesis and organization of articular cartilage matrix during inflammation. J. Cell. Physiol. 197: 357–369, 2003© 2003 Wiley‐Liss, Inc.