Cell Death Discovery ( IF 6.1 ) Pub Date : 2019-11-12 , DOI: 10.1038/s41420-019-0223-1
Rongze Wang , Yuanxu Zhang , Fujun Jin , Gongchen Li , Yao Sun , Xiaogang Wang
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Type 1 diabetes mellitus (T1DM) is an autoimmune insulin-dependent disease associated with destructive bone homeostasis. Accumulating evidence has proven that miRNAs are widely involved in the regulation of bone homeostasis. However, whether miRNAs also regulate osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in T1DM mice is under exploration. In this study, miRNA microarray was utilized to screen the differentially expressed miRNAs, which uncovered that miR-214-3p potentially inhibited BMSCs osteogenic differentiation in T1DM mice. We found that high glucose suppressed BMSCs osteogenic differentiation with significant elevation of the miR-214-3p expression. Further study found that the osteogenic differentiation of BMSCs was inhibited by AgomiR-214-3p while enhanced by AntagomiR-214-3p in BMSCs supplemented with high glucose. Moreover, we found that miR-214-3p knockout T1DM mice were resistant to high-glucose-induced bone loss. These results provide a novel insight into an inhibitory role of high-glucose-induced miR-214-3p in BMSCs osteogenic differentiation both in vitro and in vivo. Molecular studies revealed that miR-214-3p inhibits BMSCs osteogenic differentiation by targeting the 3′-UTR of β-catenin, which was further corroborated in human bone specimens and BMSCs of T1DM patients. Taken together, our study discovered that miR-214-3p is a pivotal regulator of BMSCs osteogenic differentiation in T1DM mice. Our findings also suggest that miR-214-3p could be a potential target in the treatment of bone disorders in patients with T1DM.
中文翻译:
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高糖诱导的miR-214-3p抑制BMSCs在1型糖尿病中的成骨分化
1型糖尿病(T1DM)是与破坏性骨稳态相关的自身免疫胰岛素依赖性疾病。越来越多的证据证明,miRNA广泛参与骨稳态的调节。但是,miRNA是否也能调节T1DM小鼠骨髓间充质干细胞(BMSCs)的成骨分化。在这项研究中,miRNA微阵列被用于筛选差异表达的miRNA,这揭示了miR-214-3p可能抑制T1DM小鼠的BMSCs成骨分化。我们发现,高糖抑制了BMSCs的成骨分化,并显着提高了miR-214-3p表达。进一步的研究发现,在补充高糖的BMSCs中,AgomiR-214-3p抑制了BMSCs的成骨分化,而AntagomiR-214-3p增强了BMSCs的成骨分化。此外,我们发现miR-214-3p敲除的T1DM小鼠对高糖诱导的骨质流失具有抵抗力。这些结果为体内和体外高糖诱导的miR-214-3p在BMSCs成骨分化中的抑制作用提供了新的见解。分子研究表明,miR-214-3p通过靶向β-catenin的3'-UTR抑制BMSCs的成骨分化,这一点在人骨标本和T1DM患者的BMSCs中得到了进一步证实。综上所述,我们的研究发现miR-214-3p是T1DM小鼠中BMSCs成骨分化的关键调节剂。