Abstract
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.
Highlights
Throughout life, the bones are constantly remodeled by means of two coordinated and synchronized processes, including osteoblast-driven bone formation and osteoclast-driven bone resorption
The results showed that the expression of Runx2, Osx, and alkaline phosphatase (Alp) (Fig. 1a), the enzyme activity of Alkaline phosphatase (ALP) (Fig. 1b), the protein expression of Runt-related transcription factor 2 (RUNX2) and OSX (Fig. 1c), and the mineralized nodules of the external matrix (Fig. 1d) were all significantly miRNA-132-3p mediates the unloading effects on bone marrow-derived mesenchymal stem cells (BMSCs) osteogenic differentiation in vitro To verify whether miRNA-132-3p could respond to mechanical unloading in BMSC osteogenic differentiation, BMSCs were first exposed to a clinostatbased gravitational mechanical unloading environment and were induced into the osteogenic lineage
The expression of Runx2, Osx, and Alp (Fig. 3a, c) and the enzymatic activity of ALP (Fig. 3b) were all gradually decreased, indicating that the osteogenic differentiation process of BMSCs was blocked by the unloading conditions
Summary
Throughout life, the bones are constantly remodeled by means of two coordinated and synchronized processes, including osteoblast-driven bone formation and osteoclast-driven bone resorption. Skeletal unloading can disrupt the physiological process of bone remodeling and can induce severe bone loss, especially in weight-bearing bones This kind of bone loss, clinically termed disuse osteoporosis, is characterized by a reduction in bone mass and the deterioration of skeletal microarchitecture without a change in the bone mineral to collagen ratio [2]. It often occurs in spaceflight astronauts or in patients subjected to prolonged bed-rest or immobility [2, 3]. The aim of this study was to investigate whether miRNA-132-3p could be an effective target for treating disuse osteopenia
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