Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of expression of c-fos gene on proteoglycan synthesis, one of the important markers of cartilage metabolism, was examined by introducing the c-fos DNA into HCS 2/8 chondrocytes. The [35S]sulfate incorporation into proteoglycan was decreased in the c-fos transfectants expressing exogenous c-fos mRNA, when compared to a control transfectant. A significant increase in transcription of MMP-3 with the suppressed transcription of aggrecan and TIMP-1 were also observed in the c-fos transfectants. Moreover, analysis of the effect of AP-1 proteins on the collagenase and TIMP-1 promoters in gastric carcinoma KKLS cells revealed that c-Fos combined with any of the Jun-related proteins failed to stimulate the TIMP-1 promoter, though collagenase promoter was effectively activated by any Fos/Jun-related protein heterocomplex. These findings indicate that the c-fos expression may govern the cartilage metabolism and hence may play an important role in the pathogenesis of joint destruction in arthritis.
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PMID:Expression of c-fos gene inhibits proteoglycan synthesis in transfected chondrocyte. 860 60

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 kappaB (NF-kappaB) 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), 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-kappaB. IkappaB-alpha and IkappaB-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 IkappaB-alpha and IkappaB-beta and prevented the TNF-alpha-dependent nuclear translocation of p65. Furthermore, the inhibitors completely prevented the TNF-alpha-dependent induction of MMP-1, MMP-3, ICAM-1, and COX-2 mRNAs. Thus, it is shown that the activation of p65/p50 NF-kappaB by TNF-alpha 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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PMID:Tumor necrosis factor alpha induces expression of genes for matrix degradation in human chondrocyte-like HCS-2/8 cells through activation of NF-kappaB: abrogation of the tumor necrosis factor alpha effect by proteasome inhibitors. 1145 Jul 3