TET3 Mediates Alterations in the Epigenetic Marker 5hmC and Akt pathway in Steroid‐Associated Osteonecrosis
TET3 Mediates Alterations in the Epigenetic Marker 5hmC and Akt pathway in Steroid‐Associated Osteonecrosis
复制标题
DOI：
10.1002/jbmr.2992
复制
发表时间：
2017-02
影响因子：
6.2
通讯作者：
Jie Zhao;Xin-long Ma;Jian-xiong Ma;Lei Sun;Bin Lu;Y. Wang;Guosheng Xing;Yan Wang;Ben‐chao Dong
中科院分区：
文献类型：
--
作者：
Jie Zhao;Xin-long Ma;Jian-xiong Ma;Lei Sun;Bin Lu;Y. Wang;Guosheng Xing;Yan Wang;Ben‐chao Dong
类固醇相关性骨坏死（SAON）是临床糖皮质激素（GC）给药的常见并发症之一，骨细胞凋亡是主要的组织病理学病变。然而，SAON的确切机制仍然未知。表观遗传修饰可能是SAON的主要原因。最近，累积的研究表明，10 - 11易位（泰特）蛋白可以催化5-甲基胞嘧啶（5 mC）转化为5-羟甲基胞嘧啶（5 hmC），然后改变DNA的表观遗传状态。在这里，我们报告了TET 3 - 5 hmC在SAON患者的股骨头组织和地塞米松（Dex）治疗的MLO-Y 4细胞中上调。MLO-Y 4细胞中TET 3的敲低降低了5 hmC富集并挽救了Dex诱导的细胞凋亡。同时，在Sprague-道利大鼠中局部髓内注射TET 3 siRNA消除了体内GC诱导的股骨头中骨细胞凋亡、组织病理学改变、异常MRI信号和骨微结构下降。此外，Dex处理的骨细胞的羟甲基化DNA免疫沉淀（hMeDIP）芯片分析显示了456种不同的5 hmC富集基因。发现Akt通路介导Dex诱导的动态5 hmC变化的功能效应;这在临床样本中得到进一步验证。MLO-Y 4细胞中TET 3的缺失消除了Dex诱导的Akt信号通路抑制。因此，我们的数据首次确定了TET 3 - 5 hmC对Akt通路的影响以及SAON中这种信号级联的必要性，确定了一个新的潜在治疗靶点。© 2016美国骨与矿物质研究学会。
Steroid‐associated osteonecrosis (SAON) is one of the common complications of clinical glucocorticoid (GC) administration, with osteocyte apoptosis appearing as the primary histopathological lesion. However, the precise mechanism underlying SAON remains unknown. Epigenetic modification may be a major cause of SAON. Recently, cumulative research revealed that Ten‐Eleven Translocation (TET) proteins can catalyze the conversion of 5‐methylcytosine (5mC) to 5‐hydroxymethylcytosine (5hmC) and then alter the epigenetic state of DNA. Here, we report that TET3‐5hmC was upregulated in the femoral head tissues of SAON patients and MLO‐Y4 cells with dexamethasone (Dex) treatment. Knockdown of TET3 in MLO‐Y4 cells decreased 5hmC enrichment and rescued Dex‐induced apoptosis. Meanwhile, the local intramedullary injection of TET3 siRNA in Sprague‐Dawley rats abrogated GC‐induced osteocyte apoptosis, histopathological changes, abnormal MRI signals, and bone microstructure declines in the femoral head in vivo. Moreover, a hydroxymethylated DNA immunoprecipitation (hMeDIP)‐chip analysis of Dex‐treated osteocytes revealed 456 different 5hmC‐enriched genes. The Akt pathway was found to mediate the functional effect of Dex‐induced dynamic 5hmC change; this was further verified in clinical samples. The loss of TET3 in MLO‐Y4 cells abrogated Dex‐induced Akt signaling pathway inhibition. Therefore, our data for the first time identify the effect of TET3‐5hmC on the Akt pathway and the necessity of this signaling cascade in SAON, identifying a new potential therapeutic target. © 2016 American Society for Bone and Mineral Research.