miR-129-5p Inhibits Bone Formation Through TCF4.
miR-129-5p Inhibits Bone Formation Through TCF4.
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miR-129-5p 通过 TCF4 抑制骨形成
DOI：
10.3389/fcell.2020.600641
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发表时间：
2020
影响因子：
5.5
通讯作者：
Qian A
中科院分区：
文献类型：
--
作者：
Yin C;Tian Y;Yu Y;Yang C;Su P;Zhao Y;Wang X;Zhang K;Pei J;Li D;Chen Z;Zhang Y;Miao Z;Qian A
骨质疏松症是一种多发于中老年男性和女性的骨骼疾病。然而，目前对这种疾病的治疗仍然不理想。microRNA（miRNAs）是一类长度为18-25个核苷酸的内源性非蛋白质编码RNA。miRNAs已被鉴定为发育、代谢、致癌和骨形成的重要调节因子。miR-129- 5 p已被报道为癌症和神经科学的调节剂，而关于其在骨形成中的功能的研究仍然有限。本研究旨在探讨miR-129- 5 p在成骨细胞分化和骨形成中的作用及其机制。我们评估了衰老和绝经骨质疏松症C57 BL 6小鼠骨髓间充质干细胞中miRNA的表达。在所有骨质疏松模型中，miR-129- 5 p的表达均发生改变。不同年龄C57 BL/6小鼠股骨组织中miR-129- 5 p的表达与成骨分化标志物呈负相关。我们进一步证明了miR-129- 5 p的过表达抑制了MC 3 T3-E1细胞系中的成骨细胞分化以及C57 BL/6小鼠的骨形成。另一方面，下调miR-129- 5 p可促进成骨细胞分化和骨形成。我们还发现miR-129- 5 p抑制成骨细胞中的Wnt/β-catenin通路。miR-129- 5 p的靶基因被预测并证实为Tcf 4。我们进一步发现含Tcf 4 -3′ UTR序列的质粒促进了MC 3 T3-E1细胞的成骨分化，同时也促进了Wnt/β-catenin信号通路。为了进一步研究miR-129- 5 p抑制剂的拯救作用，我们通过大肠杆菌系统制备了新型的生物工程重组miR-129- 5 p抑制剂，并对其功能进行了检测。结果表明，新型重组miR-129- 5 p抑制剂可促进C57 BL 6小鼠成骨细胞分化，并显著改善绝经期骨质疏松症。总之，我们发现miR-129- 5 p是骨形成的抑制剂。miR-129- 5 p通过靶向Tcf 4抑制Wnt/β-catenin通路下游转录因子。此外，新型重组miR-129- 5 p抑制剂显示出对骨质疏松症的挽救作用。该研究揭示了成骨分化的新机制，为骨骼疾病的治疗提供了新的治疗策略。
Osteoporosis is a frequently occurring bone disease in middle-aged and aged men and women. However, current therapies on this disease are still not ideal. MicroRNAs (miRNAs) are a class of endogenous non-protein-coding RNA with a length of 18–25 nucleotides. miRNAs have been identified as important regulators for development, metabolism, carcinogenesis, and bone formation. miR-129-5p has been reported as a regulator of cancer and neuroscience, whereas studies about its function on bone formation is still limited. In this study, we investigated the function and mechanism of miR-129-5p on osteoblast differentiation and bone formation. We have assessed the expression of miRNAs in bone mesenchymal stem cells from aging and menopause osteoporosis C57BL6 mice. The expression of miR-129-5p was altered in all osteoporosis models. Besides, the expression of miR-129-5p was negatively correlated with osteoblastic differentiation markers in the femur tissues of C57BL/6 mice of different ages. We further demonstrated that overexpression of miR-129-5p inhibited osteoblast differentiation in MC3T3-E1 cell line, as well as bone formation of C57BL/6 mice. On the other hand, down-regulation of miR-129-5p enhanced osteoblast differentiation and bone formation. We also found that miR-129-5p inhibited Wnt/β-catenin pathway in osteoblast. The target gene of miR-129-5p has been forecasted and proved as Tcf4. We further found that plasmid containing Tcf4–3′ UTR sequence enhanced osteoblast differentiation, as well as Wnt/β-catenin pathway in MC3T3-E1 cells. To further investigate the rescue effect of miR-129-5p inhibitor, we manufactured bioengineered novel recombinant miR-129-5p inhibitor through Escherichia coli system and then tested its function. The results showed that the novel recombinant miR-129-5p inhibitor promoted osteoblast differentiation and greatly ameliorated menopause osteoporosis in C57BL6 mice. In conclusion, we have discovered miR-129-5p as an inhibitor of bone formation. miR-129-5p inhibited downstream transcription factors of Wnt/β-catenin pathway through targeting Tcf4. Moreover, novel recombinant miR-129-5p inhibitor showed rescue effect on osteoporosis. This study has revealed a new mechanism of osteogenic differentiation and provided novel therapeutic strategies for treatment of skeletal disorders.
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