Department of Endocrinology, The Affiliated Lianshui County People's Hospital of Kangda College of Nanjing Medical University, Huai'an, Jiangsu 223400, China.
Department of Imaging, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, Jiangsu 223002, China.
J Biochem. 2020 Jun 1;167(6):613-621. doi: 10.1093/jb/mvaa011.
Diabetic osteoporosis (DOP) is attributed to the aberrant physiological function of bone marrow mesenchymal stem cells (BMSCs) under high glucose (HG) environment. MicroRNAs (miRNAs) are involved in the pathological processes of DOP. We aimed to explore the underlying mechanism of miRNA in DOP. BMSCs were cultured in osteogenic medium with HG to induce osteogenic differentiation, and the interaction between miR-493-5p and ZEB2 was assessed by luciferase assay. Herein, we found miR-493-5p is gradually reduced during osteogenic differentiation in BMSCs. HG treatment inhibits osteogenic differentiation and induces an up-regulation of miR-493-5p leading to reduced level of its downstream target ZEB2. Inhibition of miR-493-5p attenuates HG-induced osteogenic differentiation defects by upregulation of ZEB2. Mechanistically, miR-493-5p/ZEB2 signalling mediates HG-inhibited osteogenic differentiation by inactivation of Wnt/β-catenin signalling. More importantly, knockdown of miR-493-5p therapeutically alleviated the DOP condition in mice. HG prevents BMSCs osteogenic differentiation via up-regulation of miR-493-5p, which results in reduced level of ZEB2 by directly targeting its 3'-untranslated region of mRNA. Thus, miR-493-5p/ZEB2 is a potential therapeutic target and provides novel strategy for the treatment and management of DOP.
糖尿病性骨质疏松症 (DOP) 归因于高糖 (HG) 环境下骨髓间充质干细胞 (BMSCs) 的异常生理功能。MicroRNAs (miRNAs) 参与 DOP 的病理过程。我们旨在探讨 miRNA 在 DOP 中的潜在机制。BMSCs 在成骨培养基中培养并接受 HG 处理以诱导成骨分化，并通过荧光素酶测定评估 miR-493-5p 与 ZEB2 之间的相互作用。在此，我们发现 miR-493-5p 在 BMSCs 的成骨分化过程中逐渐减少。HG 处理抑制成骨分化并诱导 miR-493-5p 的上调，导致其下游靶标 ZEB2 的水平降低。抑制 miR-493-5p 通过上调 ZEB2 减轻 HG 诱导的成骨分化缺陷。机制上，miR-493-5p/ZEB2 信号通过失活 Wnt/β-catenin 信号转导介导 HG 抑制的成骨分化。更重要的是，miR-493-5p 的敲低治疗性地缓解了小鼠的 DOP 状况。HG 通过上调 miR-493-5p 来阻止 BMSCs 的成骨分化，这导致 ZEB2 的水平降低，这是通过直接靶向其 mRNA 的 3'非翻译区实现的。因此，miR-493-5p/ZEB2 是一个有潜力的治疗靶点，并为 DOP 的治疗和管理提供了新策略。
