Targeted silencing of miRNA-132-3p expression rescues disuse osteopenia by promoting mesenchymal stem cell osteogenic differentiation and osteogenesis in mice

• Published in: Stem cell research & therapy Vol. 11; no. 1; pp. 58 - 15
• Main Authors: Hu, Zebing, Zhang, Lijun, Wang, Han, Wang, Yixuan, Tan, Yingjun, Dang, Lei, Wang, Ke, Sun, Zhongyang, Li, Gaozhi, Cao, Xinsheng, Zhang, Shu, Shi, Fei, Zhang, Ge
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 13.02.2020; BioMed Central; BMC
• Subjects: Adipocytes; Analysis; Animals; Antagonists; Astronauts; BMSCs; Bone density; Bone Diseases, Metabolic - metabolism; Bone growth; Bone marrow; Bone mass; Cell differentiation; Cell Differentiation - physiology; Disease Models, Animal; Disuse osteopenia; Down-Regulation; Experiments; Gravity; Male; Mechanical properties; Mechanical unloading; Mesenchymal stem cells; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred C57BL; MicroRNA; MicroRNAs - metabolism; Mineralization; miRNA; Osteogenesis; Osteogenic differentiation; Osteopenia; Osteoporosis; Polyclonal antibodies; Proteins; Scientific equipment industry; Space flight; Stem cell transplantation; Stem cells; Targeted delivery; Therapeutic applications; United States; United States > US; China; miRNA; Targeted delivery; Osteogenic differentiation; BMSCs; Disuse osteopenia
• DOI: 10.1186/s13287-020-1581-6
• ISSN: 1757-6512

Skeletal 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. The 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) -cationic liposome system. The bone mass, microstructure, and strength of the hindlimb bone tissue were analyzed for evaluating the therapeutic effect in vivo. miRNA-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. The 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.