Abstract
Mounting evidence indicates that microRNAs (miRNAs) are involved in multiple processes of osteogenic differentiation. MicroRNA-101 (miR-101), identified as a tumor suppressor, has been implicated in the pathogenesis of several types of cancer. However, the expression of miR-101 and its roles in the osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs) remain unclear. We found that the miR-101 expression level was significantly increased during the osteogenic differentiation of hBMSCs. MiR-101 depletion suppressed osteogenic differentiation, whereas the overexpression of miR-101 was sufficient to promote this process. We further demonstrated that enhancer of zeste homolog 2 (EZH2) was a target gene of miR-101. EZH2 overexpression and depletion reversed the promoting or suppressing effect of osteogenic differentiation of hBMSCs, respectively, caused by miR-101. In addition, we showed that miR-101 overexpression promoted the expression of Wnt genes, resulting in the activation of the Wnt/β-catenin signaling pathway by targeting EZH2, while the activity of β-catenin and the Wnt/β-catenin signaling pathway was inhibited by ICG-001, a β-Catenin inhibitor, which reversed the promoting effect of miR-101. Finally, miR-101 also promotes in vivo bone formation by hBMSCs. Collectively, these data suggest that miR-101 is induced by osteogenic stimuli and promotes osteogenic differentiation at least partly by targeting the EZH2/Wnt/β-Catenin signaling pathway.
Highlights
Bone marrow-derived mesenchymalstem cells (MSCs) are multipotent stromal cells that have the capability to differentiate into a variety of cell types including osteoblasts[1]
Expression of miR-101 is increased during osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs)
To investigate whether miR-101 is involved in regulating osteogenic differentiation, hBMSCs were cultured in osteogenic differentiation medium
Summary
Bone marrow-derived mesenchymalstem cells (MSCs) are multipotent stromal cells that have the capability to differentiate into a variety of cell types including osteoblasts[1]. Increasing evidence shows that posttranslational repression of gene expression mediated by miRNAs, plays an important role in regulating the osteogenic differentiation of MSCs5,6. Further investigation is required to clarify whether the osteogenic differentiation is regulated by other miRNAs. MiR-101, frequently silenced in human cancers, has been shown to have fundamental roles in diverse cellular processes, especially in the control of proliferation and differentiation[12,13,14,15]. EZH2, which plays an important biological role, has been reported to be a target gene of miR-101 in various cells. The aims of the present study were to explore the expression and role of miR-101 in the osteogenic differentiation of hBMSCs, to investigate whether miR-101 regulates osteogenic differentiation by targeting EZH2 and to validate the regulatory relationship betweenmiR-101 and the Wnt/β-Catenin signaling pathway
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