Epigenetic inhibition of Wnt pathway suppresses osteogenic differentiation of BMSCs during osteoporosis.
Epigenetic inhibition of Wnt pathway suppresses osteogenic differentiation of BMSCs during osteoporosis.
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Wnt 通路的表观遗传抑制抑制骨质疏松期间 BMSC 的成骨分化
DOI：
10.1038/s41419-017-0231-0
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发表时间：
2018-02-07
影响因子：
9
通讯作者：
Jin Y
中科院分区：
文献类型：
--
作者：
Jing H;Su X;Gao B;Shuai Y;Chen J;Deng Z;Liao L;Jin Y
成骨细胞系中Wnt信号传导中断导致骨质疏松症中骨形成缺陷。然而，抑制Wnt信号传导的因素尚不清楚。在我们的研究中，我们发现在骨质疏松症期间，Wnt信号在骨髓间充质干细胞（BMSCs）中持续受到抑制。相应地，去卵巢小鼠骨髓间充质干细胞中Wnt基因（Wnt 1、Wnt 6、Wnt 10a和Wnt 10b）上的组蛋白乙酰化水平下降。通过筛选组蛋白乙酰转移酶家族，我们发现GCN 5在BMSCs成骨分化过程中表达增加，而在骨质疏松后表达下降。进一步分析表明GCN 5通过增加Wnt基因启动子上组蛋白3赖氨酸9位点的乙酰化来促进BMSCs的成骨分化。GCN 5表达减少抑制Wnt信号传导，导致OVX小鼠BMSCs成骨缺陷。此外，恢复GCN 5水平可以恢复BMSC的成骨分化，并减轻OVX小鼠的骨丢失。综上所述，我们的研究表明，在骨质疏松症中，BMSCs中组蛋白乙酰化修饰被破坏导致骨形成缺陷。这些发现还为骨质疏松症引入了一种新的治疗靶点。
Disrupted Wnt signaling in osteoblastic-lineage cells leads to bone formation defect in osteoporosis. However, the factors repressing Wnt signaling are unclear. In our study, we found that Wnt signaling was suppressed persistently in bone marrow-derived mesenchymal stem cells (BMSCs) during osteoporosis. Accordingly, histone acetylation levels onWntgenes (Wnt1,Wnt6,Wnt10a, andWnt10b) were declined in BMSCs from OVX mice. By screening the family of histone acetyltransferase, we identified that GCN5 expression increased during osteogenic differentiation of BMSCs, whereas decreased after osteoporosis. Further analysis revealed that GCN5 promoted osteogenic differentiation of BMSCs by increasing acetylation on histone 3 lysine 9 loci on the promoters of Wnt genes. Reduced GCN5 expression suppressed Wnt signaling, resulting in osteogenic defect of BMSCs from OVX mice. Moreover, restoring GCN5 levels recovered BMSC osteogenic differentiation, and attenuated bone loss in OVX mice. Taken together, our study demonstrated that disrupted histone acetylation modification in BMSCs lead to bone formation defect during osteoporosis. The findings also introduced a novel therapeutic target for osteoporosis.
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影响因子：
12.4
作者：
Li, Yan;Fan, Longkun;Jin, Yan
通讯作者：
Jin, Yan
DOI：
10.1016/j.bbrc.2014.10.021
发表时间：
2014-10-31
影响因子：
3.1
作者：
Huang, Xiaoju;Xu, Jiajia;Zhang, Xiaoling
通讯作者：
Zhang, Xiaoling
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影响因子：
23.9
作者：
Wang, Hu;Diao, Daojun;Ju, Zhenyu
通讯作者：
Ju, Zhenyu
影响因子：
7.8
作者：
Moerman, EJ;Teng, K;Lecka-Czernik, B
通讯作者：
Lecka-Czernik, B
影响因子：
3.7
作者：
Todd H;Galea GL;Meakin LB;Delisser PJ;Lanyon LE;Windahl SH;Price JS
通讯作者：
Price JS