miR-206 inhibits osteogenic differentiation of bone marrow mesenchymal stem cells by targetting glutaminase
miR-206 inhibits osteogenic differentiation of bone marrow mesenchymal stem cells by targetting glutaminase
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DOI：
10.1042/bsr20181108
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发表时间：
2019-03-29
影响因子：
4
通讯作者：
Xu, Xiao-Dong
中科院分区：
文献类型：
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作者：
Chen, Ying;Yang, Yu-Run;Xu, Xiao-Dong
成骨细胞介导的骨形成是一个复杂的过程，涉及各种途径和调节因子，包括细胞因子，生长因子和激素。研究成骨细胞分化的调控机制对骨再生治疗具有重要意义。miRNAs不仅在多种细胞过程中发挥重要的调节作用，而且在骨疾病的发病机制中发挥重要作用。在本研究中，我们研究了miR-206在成骨细胞分化过程中的潜在作用。我们报道了在成骨诱导过程中，miR-206在人骨髓间充质干细胞（BMSCs）中的表达在第7天和第14天显著下调。此外，过表达miR-206的BMSCs显示碱性磷酸酶（ALP）活性、茜素红染色和骨钙素分泌减弱。成骨标志物Runx2和骨桥蛋白（OPN）的mRNA水平在miR-206过表达的BMSCs中显著下调。我们观察到，显着增加谷氨酰胺摄取在第7和14天，在成骨诱导和抑制谷氨酰胺代谢敲低谷氨酰胺酶（GLS）抑制成骨分化的BMSCs。在此，我们发现miR-206可以直接与GLS mRNA的3'-UTR区域结合，导致GLS表达和谷氨酰胺代谢受到抑制。最后，在miR-206过表达的BMSC中GLS的恢复导致谷氨酰胺代谢和成骨分化的恢复。综上所述，这些结果揭示了miR-206通过调节谷氨酰胺代谢介导的成骨机制的新见解。我们的研究可能有助于开发针对骨疾病的治疗药物。
Osteoblast-mediated bone formation is a complex process involving various pathways and regulatory factors, including cytokines, growth factors, and hormones. Investigating the regulatory mechanisms behind osteoblast differentiation is important for bone regeneration therapy. miRNAs are known as important regulators, not only in a variety of cellular processes, but also in the pathogenesis of bone diseases. In the present study, we investigated the potential roles of miR-206 during osteoblast differentiation. We report that miR-206 expression was significantly down-regulated in human bone marrow mesenchymal stem cells (BMSCs) at days 7 and 14 during osteogenic induction. Furthermore, miR-206 overexpressing BMSCs showed attenuated alkaline phosphatase (ALP) activity, Alizarin Red staining, and osteocalcin secretion. The mRNA levels of osteogenic markers, Runx2 and Osteopontin (OPN), were significantly down-regulated in miR-206 overexpressing BMSCs. We observed that significantly increased glutamine uptake at days 7 and 14 during the osteogenic induction and inhibition of glutamine metabolism by knocking down glutaminase (GLS)-suppressed osteogenic differentiation of BMSCs. Here, we discover that miR-206 could directly bind to the 3'-UTR region of GLS mRNA, resulting in suppressed GLS expression and glutamine metabolism. Finally, restoration of GLS in miR-206 overexpressing BMSCs led to recovery of glutamine metabolism and osteogenic differentiation. In summary, these results reveal a new insight into the mechanisms of the miR-206-mediated osteogenesis through regulating glutamine metabolism. Our study may contribute to the development of therapeutic agents against bone diseases.