期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 24, 页码 17552-17558出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.453985
关键词
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资金
- BioMedical Materials Institute [P2.02]
- Dutch Ministry of Economic Affairs, Agriculture, and Innovation
T cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors are downstream effectors of Wnt/beta-catenin signaling, which has been implicated in the development and progression of osteoarthritis (OA). This study aimed to investigate the role of TCF/LEF transcription factors in human articular chondrocytes. Primary human osteoarthritic cartilage predominantly expressed TCF4 and to a lesser extent, LEF1 and TCF3 mRNA. Overexpression of TCF4, but not of TCF3 or LEF1, induced MMP-1, -3, and -13 expression and generic MMP activity in human chondrocytes. This was due to potentiating NF-kappa B signaling by a protein-protein interaction between TCF4 and NF-kappa B p65 activating established NF-kappa B target genes such as MMPs and IL-6. LEF1 competed with TCF4 for binding to NF-kappa B p65. I kappa B-alpha was able to counteract the effect of TCF4 on NF-kappa B target gene expression. Finally, we showed that TCF4 mRNA expression was elevated in OA cartilage compared with healthy cartilage and induced chondrocyte apoptosis at least partly through activating caspase 3/7. Our findings suggest that increased TCF4 expression may contribute to cartilage degeneration in OA by augmenting NF-kappa B signaling.
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