MicroRNA-133a Regulates the Viability and Differentiation Fate of Bone Marrow Mesenchymal Stem Cells via MAPK/ERK Signaling Pathway by Targeting FGFR1
MicroRNA-133a Regulates the Viability and Differentiation Fate of Bone Marrow Mesenchymal Stem Cells via MAPK/ERK Signaling Pathway by Targeting FGFR1
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DOI：
10.1089/dna.2021.0206
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发表时间：
2021-06-24
影响因子：
3.1
通讯作者：
Zhang, Yuelei
中科院分区：
文献类型：
--
作者：
Wang, Gang;Wan, Lifu;Zhang, Yuelei
骨髓间充质干细胞（BMSCs）功能障碍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-133 a（miR-133 a）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-133 a的过表达或敲低而导致的BMSC的细胞增殖、细胞凋亡和成骨细胞/脂肪细胞分化。在体内研究中，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-133 a阿托洛尔进一步治疗模型。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。结果显示，miR-133 a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FGFR 1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-133 a的主要作用靶点。我们还记录了骨髓基质细胞特异性敲低miR-133 a可减轻OVX小鼠的骨丢失。我们的研究表明，miR-133 a通过MAPK/ERK信号通路靶向FGFR 1，在维持BMSCs成骨细胞和脂肪细胞分化的活力和平衡中发挥重要作用。
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.