TWIST1 induces MMP3 expression through up-regulating DNA hydroxymethylation and promotes catabolic responses in human chondrocytes.
TWIST1 induces MMP3 expression through up-regulating DNA hydroxymethylation and promotes catabolic responses in human chondrocytes.
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DOI：
10.1038/srep42990
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发表时间：
2017-02-21
影响因子：
4.6
通讯作者：
Asahara H
中科院分区：
文献类型：
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作者：
Hasei J;Teramura T;Takehara T;Onodera Y;Horii T;Olmer M;Hatada I;Fukuda K;Ozaki T;Lotz MK;Asahara H
目的是研究TWIST 1在正常和OA软骨中的水平，并检查其在软骨细胞中调节基因表达的作用。人软骨组织和软骨细胞是在尸检时从正常膝关节和全膝关节置换术时OA影响的关节获得的。与正常膝关节软骨相比，TWIST 1在人OA膝关节软骨中的表达增加。TWIST 1诱导基质金属蛋白酶3（MMP 3）的表达，而不直接结合MMP 3启动子，并增加5-羟甲基胞嘧啶（5 hmC）在MMP 3启动子的水平。在稳定转染TWIST 1的TC 28细胞中检测TWIST 1对泰特家族（TET 1、2和3）表达的影响，并且TET 1表达上调。在源自小鼠ES细胞的泰特三重KO成纤维细胞中，Mmp 3表达的TWIST 1依赖性上调被抑制。TWIST 1表达增加是OA影响的软骨的一个特征。我们确定了一种新的分解代谢反应机制，其中TWIST 1通过TET 1诱导在MMP 3启动子处富集5 hmC水平来上调MMP 3表达。这些发现暗示TWIST 1是调节OA相关基因表达的重要因子。阐明TWIST 1诱导的5 hmC的表观遗传机制是了解OA发病机制的关键分子。
The objective was to investigate the levels of TWIST1 in normal and OA cartilage and examine its role in regulating gene expression in chondrocytes. Human cartilage tissues and chondrocytes were obtained at autopsy from normal knee joints and from OA-affected joints at the time of total knee arthroplasty. TWIST1 expression was increased in human OA knee cartilage compared to normal knee cartilage. TWIST1 induced matrix metalloproteinase 3 (MMP3) expression without direct binding to MMP3 promoter and increased the 5-hydroxymethylcytosine (5hmC) level at the MMP3 promoter. The effect of TWIST1 on expression of TET family (TET1, 2 and 3) was measured in stable TWIST1 transfected TC28 cells, and TET1 expression was up-regulated. TWIST1 dependent upregulation of Mmp3 expression was suppressed in Tet triple KO fibroblast derived from mouse ES cells. Increased TWIST1 expression is a feature of OA-affected cartilage. We identified a novel mechanism of catabolic reaction where TWIST1 up-regulates MMP3 expression by enriching 5hmC levels at the MMP3 promoter via TET1 induction. These findings implicate TWIST1 as an important factor regulating OA related gene expression. Clarifying epigenetic mechanisms of 5hmC induced by TWIST1 is a critical molecule to understanding OA pathogenesis.