miR-601 诱导的骨髓间充质干细胞衰老通过靶向 SIRT1 加速激素性股骨头坏死的进展。
MiR-601-induced BMSCs senescence accelerates steroid-induced osteonecrosis of the femoral head progression by targeting SIRT1.
机构信息
Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400000, China.
Orthopedic Laboratory of Chongqing Medical University, Chongqing, China.
出版信息
Cell Mol Life Sci. 2023 Aug 19;80(9):261. doi: 10.1007/s00018-023-04903-8.
BACKGROUND
The imbalance between osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is not only the primary pathological feature but also a major contributor to the pathogenesis of steroid-induced osteonecrosis of the femoral head (SONFH). Cellular senescence is one of the main causes of imbalanced BMSCs differentiation. The purpose of this study was to reveal whether cellular senescence could participate in the progression of SONFH and the related mechanisms.
METHODS
The rat SONFH model was constructed, and rat BMSCs were extracted. Aging-related indicators were detected by SA-β-Gal staining, qRT-PCR and Western Blot experiments. Using HO to construct a senescent cell model, and overexpressing and knocking down miR-601 and SIRT1 in hBMSCs, the effect on BMSCs differentiation was explored by qRT-PCR, Western Blot experiment, oil red O staining (ORO), alizarin red staining (ARS), and luciferase reporter gene experiment. A rat SONFH model was established to test the effects of miR-601 and metformin in vivo.
RESULTS
The current study showed that glucocorticoids (GCs)-induced BMSCs senescence, which caused imbalanced osteogenesis and adipogenesis of BMSCs, was responsible for the SONFH progression. Further, elevated miR-601 caused by GCs was demonstrated to contribute to BMSCs senescence through targeting SIRT1. In addition, the anti-aging drug metformin was shown to be able to alleviate GCs-induced BMSCs senescence and SONFH progression.
CONCLUSIONS
Considering the role of BMSCs aging in the progression of SONFH, this provides a new idea for the prevention and treatment of SONFH.
背景
骨髓间充质干细胞（BMSCs）成骨与成脂分化失衡不仅是主要的病理特征，也是导致激素性股骨头坏死（SONFH）发病的主要原因。细胞衰老也是 BMSCs 分化失衡的主要原因之一。本研究旨在探讨细胞衰老是否参与 SONFH 的进展及其相关机制。
方法
构建大鼠 SONFH 模型，提取大鼠 BMSCs，采用 SA-β-Gal 染色、qRT-PCR 和 Western blot 实验检测衰老相关指标。利用 HO 构建衰老细胞模型，在 hBMSCs 中转染 miR-601 过表达和敲低质粒及 SIRT1 过表达质粒，通过 qRT-PCR、Western blot 实验、油红 O（ORO）染色、茜素红染色（ARS）和荧光素酶报告基因实验探究其对 BMSCs 分化的影响。建立大鼠 SONFH 模型，检测 miR-601 和二甲双胍在体内的作用。
结果
本研究表明，糖皮质激素（GCs）诱导的 BMSCs 衰老导致 BMSCs 成骨和成脂分化失衡，进而导致 SONFH 进展。进一步研究表明，GCs 诱导的 miR-601 升高通过靶向 SIRT1 促进 BMSCs 衰老。此外，抗衰老药物二甲双胍能够减轻 GCs 诱导的 BMSCs 衰老和 SONFH 进展。
结论
鉴于 BMSCs 衰老在 SONFH 进展中的作用，这为 SONFH 的防治提供了新的思路。
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