T Cell Factor 4 Is a Pro-catabolic and Apoptotic Factor in Human Articular Chondrocytes by Potentiating Nuclear Factor κB Signaling
T Cell Factor 4 Is a Pro-catabolic and Apoptotic Factor in Human Articular Chondrocytes by Potentiating Nuclear Factor κB Signaling
复制标题
DOI：
10.1074/jbc.m113.453985
复制
发表时间：
2013-06-14
影响因子：
4.8
通讯作者：
Karperien, Marcel
中科院分区：
文献类型：
--
作者：
Ma, Bin;Zhong, Leilei;Karperien, Marcel
T细胞因子/淋巴增强因子（TCF/LEF）转录因子是Wnt/β-连环蛋白信号传导的下游效应因子，与骨关节炎（OA）的发生和发展有关。本研究旨在探讨TCF/LEF转录因子在人关节软骨细胞中的作用。原代人骨关节炎软骨主要表达TCF 4，LEF 1和TCF 3 mRNA表达程度较低。在人软骨细胞中，过度表达TCF 4而非TCF 3或LEF 1可诱导MMP-1、MMP-3和MMP-13的表达以及MMP的一般活性。这是由于TCF 4和NF-κ B p65之间的蛋白质-蛋白质相互作用激活了已建立的NF-κ B靶基因如MMP和IL-6，从而增强了NF-κ B信号传导。LEF 1与TCF 4竞争结合NF-κ B p65。I κ B-α能够抵消TCF 4对NF-κ B靶基因表达的影响。最后，我们发现，与健康软骨相比，OA软骨中TCF 4 mRNA的表达升高，并至少部分通过激活caspase 3/7诱导软骨细胞凋亡。我们的研究结果表明，增加TCF 4的表达可能有助于通过增加NF-κ B B信号在OA软骨退变。
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.