Targeted silencing of miRNA-132-3p expression rescues disuse osteopenia by promoting mesenchymal stem cell osteogenic differentiation and osteogenesis in mice
Targeted silencing of miRNA-132-3p expression rescues disuse osteopenia by promoting mesenchymal stem cell osteogenic differentiation and osteogenesis in mice
复制标题
靶向沉默 miRNA-132-3p 表达可通过促进小鼠间充质干细胞成骨分化和成骨来挽救废用性骨质减少。
DOI：
10.1186/s13287-020-1581-6
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发表时间：
2020-02-13
影响因子：
7.5
通讯作者：
Zhang, Ge
中科院分区：
文献类型：
--
作者：
Hu, Zebing;Zhang, Lijun;Zhang, Ge
背景骨骼卸载会导致严重的废用性骨质减少，这种情况经常发生在航天宇航员或长期卧床或不动的患者身上。以前，我们发现了一个机械敏感因子，miRNA-132- 3 p，它与成骨细胞功能密切相关。本研究的目的是调查是否miRNA-132- 3 p可以是一个有效的目标，用于治疗废用性osteopenia.MethodsThe 2D-clinostat设备和后肢卸载（HU）模型复制的机械卸载条件下，在细胞和动物水平，分别。采用miRNA-132- 3 p模拟物或抑制剂干预骨髓间充质干细胞（BMSCs）miRNA-132 - 3 p的表达，分析其对BMSCs成骨分化的影响。通过骨靶向（AspSerSer）6-阳离子脂质体系统将miRNA-132- 3 p的特异性体内拮抗剂递送到HU小鼠的骨形成区域用于治疗废用性骨质减少。结果正常情况下，骨髓基质干细胞体外成骨分化过程中，miRNA-132- 3 p表达下降，而在重力机械卸载条件下，miRNA-132- 3 p表达增加。miRNA-132- 3 p表达的上调导致成骨分化的抑制，而miRNA-132- 3 p表达的下调促进成骨分化。抑制miRNA-132- 3 p表达能够减轻机械去负荷对BMSC成骨分化的负面影响。最重要的是，靶向沉默骨组织中miRNA-132- 3 p的表达，可以通过促进HU小鼠的成骨分化和成骨，有效地保留骨量、微观结构和强度。结论机械去负荷诱导的miRNA-132- 3 p过表达不利于BMSC的成骨分化和成骨。靶向沉默miRNA-132- 3 p表达为预防和治疗废用性骨质疏松症提供了潜在的治疗靶点。
BackgroundSkeletal unloading can induce severe disuse osteopenia that often occurs in spaceflight astronauts or in patients subjected to prolonged bed-rest or immobility. Previously, we revealed a mechano-sensitive factor, miRNA-132-3p, that is closely related to the osteoblast function. The aim of this study was to investigate whether miRNA-132-3p could be an effective target for treating disuse osteopenia.MethodsThe 2D-clinostat device and the hindlimb-unloaded (HU) model were used to copy the mechanical unloading condition at the cellular and animal levels, respectively. Mimics or inhibitors of miRNA-132-3p were used to interfere with the expression of miRNA-132-3p in bone marrow-derived mesenchymal stem cells (BMSCs) in vitro for analyzing the effects on osteogenic differentiation. The special in vivo antagonists of miRNA-132-3p was delivered to the bone formation regions of HU mice for treating disuse osteopenia by a bone-targeted (AspSerSer)6-cationic liposome system. The bone mass, microstructure, and strength of the hindlimb bone tissue were analyzed for evaluating the therapeutic effect in vivo.ResultsmiRNA-132-3p expression was declined under normal conditions and increased under gravitational mechanical unloading conditions during osteogenic differentiation of BMSCs in vitro. The upregulation of miRNA-132-3p expression resulted in the inhibition of osteogenic differentiation, whereas the downregulation of miRNA-132-3p expression enhanced osteogenic differentiation. The inhibition of miRNA-132-3p expression was able to attenuate the negative effects of mechanical unloading on BMSC osteogenic differentiation. Most importantly, the targeted silencing of miRNA-132-3p expression in the bone tissues could effectively preserve bone mass, microstructure, and strength by promoting osteogenic differentiation and osteogenesis in HU mice.ConclusionThe overexpression of miRNA-132-3p induced by mechanical unloading is disadvantageous for BMSC osteogenic differentiation and osteogenesis. Targeted silencing of miRNA-132-3p expression presents a potential therapeutic target for the prevention and treatment of disuse osteoporosis.