Dysfunction of bone marrow mesenchymal stem cells (BMSCs) is recognized critical in bone deteriorations of osteoporosis. However, the specific mechanisms that determine the fate of BMSCs remain elusive. MicroRNA-133a (miR-133a), a highly conserved microRNA, was investigated under both in vitro and in vivo conditions. In the in vitro study, cell proliferation, cell apoptosis, and osteoblast/adipocyte differentiation of BMSCs as a result of overexpression or knockdown of miR-133a was investigated. In the in vivo study, the ovariectomy (OVX) model was applied on mice, with further treatment of the models with BMSC-specific miR-133a antagomir through femur intramedullary injection. Microcomputed tomography scanning and histological analysis of the proximal and middle femur were performed to evaluate the morphological changes. The results revealed that overexpression of miR-133a suppressed cell proliferation, cell viability, and osteoblast differentiation of BMSCs, but increased adipocyte differentiation. We also found that FGFR1, an important upstream regulator of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signal pathway, was a major target of miR-133a. We also recorded that BMSC-specific knockdown of miR-133a attenuates bone loss in OVX mice. Our study suggested that miR-133a played an important role in maintaining the viability and balance between osteoblast and adipocyte differentiation of BMSCs through the MAPK/ERK signaling pathway by targeting FGFR1.

中文翻译：

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MicroRNA-133a 通过靶向 FGFR1 的 MAPK/ERK 信号通路调节骨髓间充质干细胞的活力和分化命运

骨髓间充质干细胞 (BMSCs) 的功能障碍被认为是骨质疏松症骨恶化的关键。然而，决定 BMSCs 命运的具体机制仍然难以捉摸。MicroRNA-133a (miR-133a) 是一种高度保守的 microRNA，在体外和体内条件下进行了研究。在体外研究中，研究了由于 miR-133a 的过表达或敲低导致的 BMSCs 的细胞增殖、细胞凋亡和成骨细胞/脂肪细胞分化。在体内在研究中，将卵巢切除术 (OVX) 模型应用于小鼠，并通过股骨髓内注射用 BMSC 特异性 miR-133a antagomir 进一步治疗模型。对股骨近端和中段进行显微计算机断层扫描和组织学分析以评估形态学变化。结果表明，miR-133a的过表达抑制了BMSCs的细胞增殖、细胞活力和成骨细胞分化，但增加了脂肪细胞分化。我们还发现 FGFR1 是丝裂原活化蛋白激酶/细胞外信号调节激酶 (MAPK/ERK) 信号通路的重要上游调节因子，是 miR-133a 的主要靶点。我们还记录了 miR-133a 的 BMSC 特异性敲低减轻了 OVX 小鼠的骨质流失。