微小 RNA-224 在激素诱导性股骨头坏死成骨和脂生成中的相互作用。

Reciprocal effect of microRNA-224 on osteogenesis and adipogenesis in steroid-induced osteonecrosis of the femoral head.

机构信息

Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

Department of Orthopedic Surgery, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, China.

出版信息

Bone. 2021 Apr;145:115844. doi: 10.1016/j.bone.2021.115844. Epub 2021 Jan 14.

DOI:10.1016/j.bone.2021.115844

PMID:33453444

Abstract

The adverse effects of glucocorticoids (GCs) on bone marrow stromal stem cells (BMSCs) play an important role in steroid-induced osteonecrosis of the femoral head (ONFH). Our previous miRNA microarray analysis indicated that microRNA-224-5p (miR-224-5p) could be a potential regulator; however, the underlying mechanism remains unclear. In the present study, we demonstrated that miR-224-5p was upregulated in GC-treated BMSCs, and functional experiments revealed that miR-224-5p could suppress osteogenic but promote adipogenic differentiation of BMSCs. Smad4 was identified as a direct target gene of miR-224-5p, and the Smad4-Taz axis was confirmed as the regulatory pathway for adipo-osteogenic differentiation of BMSCs. Our in vivo experiments further confirmed that the miR-224-5p antagomir could alleviate the inhibitory effects of GCs and facilitate bone formation in steroid-induced ONFH models. Therefore, these findings provide insight into the function of miR-224-5p as a reciprocal regulator of the adipo-osteogenic differentiation of BMSCs, and it could serve as a novel therapeutic target for steroid-induced ONFH.

摘要

糖皮质激素（GCs）对骨髓基质干细胞（BMSCs）的不良反应在激素诱导性股骨头坏死（ONFH）中起重要作用。我们之前的 miRNA 微阵列分析表明，微小 RNA-224-5p（miR-224-5p）可能是一个潜在的调节因子；然而，其潜在机制尚不清楚。在本研究中，我们证明了 miR-224-5p 在 GC 处理的 BMSCs 中上调，功能实验表明 miR-224-5p 可以抑制成骨但促进 BMSCs 的脂肪生成分化。Smad4 被鉴定为 miR-224-5p 的直接靶基因，Smad4-Taz 轴被证实是 BMSCs 脂肪成骨分化的调节途径。我们的体内实验进一步证实，miR-224-5p 反义寡核苷酸可以减轻 GCs 的抑制作用，并促进类固醇诱导的 ONFH 模型中的骨形成。因此，这些发现为 miR-224-5p 作为 BMSCs 脂肪成骨分化的反向调节因子的功能提供了深入了解，它可能成为类固醇诱导性 ONFH 的一种新的治疗靶点。