期刊
JOURNAL OF BONE AND MINERAL RESEARCH
卷 16, 期 7, 页码 1272-1280出版社
WILEY
DOI: 10.1359/jbmr.2001.16.7.1272
关键词
chondrocytes; tumor necrosis factor alpha; nuclear factor kappa B; I kappa B; proteasome inhibitors
Tumor necrosis factor alpha (TNF-alpha) 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-alpha activates a transcription factor nuclear factor KB (NF-KB) 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-alpha markedly increased the levels of matrix metalloproteinase 1 (MMP-1), MMP3, 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-kappaB. I kappaB-alpha and I kappaB-beta, cytoplasmic molecules preventing the nuclear translocation of NF-kappaB, were degraded rapidly by TNF-alpha followed by their synthesis to the basal level. Treatment with proteasome inhibitors inhibited the degradation of both IKB-alpha and IKB-beta and prevented the TNF-alpha -dependent nuclear translocation of p65. Furthermore, the inhibitors completely prevented the TNF-alpha -dependent induction of MMP-1, MMP3, ICAM-1, and COX-2 mRNAs. Thus, it is shown that the activation of p65/p50 NF-KB by TNF-a! 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.
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