High glucose impairs osteogenic differentiation of embryonic stem cells via early diversion of beta-catenin from Forkhead box O to T cell factor interaction.
High glucose impairs osteogenic differentiation of embryonic stem cells via early diversion of beta-catenin from Forkhead box O to T cell factor interaction.
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DOI：
10.1002/bdr2.2085
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发表时间：
2022-10-01
影响因子：
2.1
通讯作者：
zur Nieden, Nicole, I
中科院分区：
文献类型：
--
作者：
Dienelt, Anke;Keller, Kevin C.;zur Nieden, Nicole, I
糖尿病的特征是血糖浓度升高，伴随着骨转换低、骨折风险增加以及胚胎骨骼畸形的形成。然而，很少有研究阐明导致这些成骨缺陷的信号通路的潜在变化。我们在此假设，高糖环境中的骨形成缺陷是由于β-连环蛋白(CTNNB1)的活性改变所致，CTNNB1是成骨分化的关键因素，其调节失调也与糖尿病的发生有关。为了验证这一假设，我们使用了先前建立的胚胎干细胞(ESC)分化模型，该模型模拟了发育中的胚胎的糖尿病环境。我们在含有高(糖尿病)或低(生理)D-葡萄糖的成骨诱导培养液中分化小鼠胚胎干细胞，并进行时间进程分析，以研究高葡萄糖对骨细胞分化的早期和晚期的影响。成骨分化的终点指标以葡萄糖依赖的方式减少，前体特异性标记物的表达在多个时间点发生变化。此外，在前体形成阶段，LEF/TCF转录因子的转录活性显著升高，而复杂的CTNNB1/FOXO3a水平下降。AKT，一个已知的LEF/TCF和FOXO3a的上游调节因子，以及CTNNB1的调节，挽救了一些在高糖条件下的成骨产量的减少。在我们的体外模型中，我们发现Lef/TCF和FOXO3a信号通路明显参与了成骨分化的调节，这可能是糖尿病母亲新生儿发现的骨骼缺陷的原因。
Diabetes, which is characterized by an increase in blood glucose concentration, is accompanied by low bone turnover, increased fracture risk, and the formation of embryonic skeletal malformations. Yet, there are few studies elucidating the underlying alterations in signaling pathways leading to these osteogenic defects. We hypothesized here that bone formation deficiencies in a high glucose environment result from altered activity of beta-catenin (CTNNB1), a key contributor to osteogenic differentiation, dysregulation of which has also been implicated in the development of diabetes. To test this hypothesis, we used a previously established embryonic stem cell (ESC) model of differentiation that mimics the diabetic environment of the developing embryo. We differentiated murine ESCs within osteogenic-inducing media containing either high (diabetic) or low (physiological) levels of D-glucose and performed time course analyses to study the influence of high glucose on early and late bone cell differentiation. Endpoint measures for osteogenic differentiation were reduced in a glucose-dependent manner and expression of precursor-specific markers altered at multiple time points. Furthermore, transcriptional activity of the LEF/TCF transcription factors during precursor formation stages was significantly elevated while levels of complexed CTNNB1/FOXO3a declined. Modulation of AKT, a known upstream regulator of both LEF/TCF and FOXO3a, as well as CTNNB1 rescued some of the reductions in osteogenic output seen in the high glucose condition. Within our in vitro model we found a clear involvement of LEF/TCF and FOXO3a signaling pathways in the regulation of osteogenic differentiation, which may account for the skeletal deficiencies found in newborns of diabetic mothers.
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影响因子：
29
作者：
Ambrogini E;Almeida M;Martin-Millan M;Paik JH;Depinho RA;Han L;Goellner J;Weinstein RS;Jilka RL;O'Brien CA;Manolagas SC
通讯作者：
Manolagas SC
影响因子：
9.5
作者：
Wang, Juan;Gu, Qi;Hao, Jie;Bai, Donghui;Liu, Lei;Zhao, Xiaoyang;Liu, Zhonghua;Wang, Liu;Zhou, Qi
通讯作者：
Zhou, Qi
DOI：
10.2106/00004623-196951040-00007
发表时间：
1969-01-01
影响因子：
5.3
作者：
BANTA, JV;NICHOLS, O
通讯作者：
NICHOLS, O
影响因子：
4.8
作者：
Cho, Cheul H.;Parashurama, Natesh;Yarmush, Martin L.
通讯作者：
Yarmush, Martin L.
影响因子：
64.5
作者：
Gong, YQ;Slee, RB;Warman, ML
通讯作者：
Warman, ML