Premium
Tumor Necrosis Factor α Induces Expression of Genes for Matrix Degradation in Human Chondrocyte‐like HCS‐2/8 Cells Through Activation of NF‐κB: Abrogation of the Tumor Necrosis Factor α Effect by Proteasome Inhibitors
Author(s) -
Sakai Tadahiro,
Kambe Fukushi,
Mitsuyama Hirohito,
Ishiguro Naoki,
Kurokouchi Kazutoshi,
Takigawa Masaharu,
Iwata Hisashi,
Seo Hisao
Publication year - 2001
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.2001.16.7.1272
Subject(s) - tumor necrosis factor alpha , chondrocyte , p50 , microbiology and biotechnology , nfkb1 , biology , matrix metalloproteinase , transcription factor , chemistry , cancer research , cartilage , immunology , biochemistry , gene , anatomy
Tumor necrosis factor α (TNF‐α) has been suggested to induce chondrocytic chondrolysis in both inflammatory and degenerative joint diseases. However, its intracellular signaling pathway leading to the chondrolysis has not been studied in detail. Thus, we investigated whether TNF‐α activates a transcription factor nuclear factor κB (NF‐κB) in human chondrocyte‐like cells (HCS‐2/8) and induces the expression of genes involved in the degradation of cartilage matrix. Treatment of the cells with TNF‐α markedly increased the levels of matrix metalloproteinase 1 (MMP‐1), MMP‐3, intercellular adhesion molecule 1 (ICAM‐1), and cyclo‐oxygenase 2 (COX‐2) messenger RNAs (mRNAs). The increase in the mRNAs was associated with the activation of p65/p50 heterodimer NF‐κB. IκB‐α and IκB‐β, cytoplasmic molecules preventing the nuclear translocation of NF‐κB, were degraded rapidly by TNF‐α followed by their synthesis to the basal level. Treatment with proteasome inhibitors inhibited the degradation of both IκB‐α and IκB‐β and prevented the TNF‐α‐dependent nuclear translocation of p65. Furthermore, the inhibitors completely prevented the TNF‐α‐dependent induction of MMP‐1, MMP‐3, ICAM‐1, and COX‐2 mRNAs. Thus, it is shown that the activation of p65/p50 NF‐κB by TNF‐α plays a cardinal role in inducing the expression of MMP‐1, MMP‐3, ICAM‐1, and COX‐2 genes, which are involved in matrix degradation and inflammatory reaction in chondrocytes, leading to chondrocytic chondrolysis.