miR-138-5p调控MACF1参与力学去负荷抑制骨形成的力生物学机制

力学刺激对骨骼系统生长发育必不可少。力学刺激的减少或缺失抑制了骨形成，导致骨质流失。microRNA作为力生物学领域的一个新热点，参与力生物学基因表达调控。申请者研究发现：miR-138-5p对力学去负荷敏感且负向调节骨形成；MACF1是miR-138-5p靶分子之一，促进成骨细胞分化。因此提出：miR-138-5p可能作为一种力敏感microRNA，通过调控MACF1参与力学去负荷抑制骨形成。本项目采用随机回转和小鼠尾悬吊力学去负荷模型，研究：(1)力学去负荷对骨形成、miR-138-5p和MACF1表达，以及Wnt/β-catenin通路的影响；(2)力学去负荷对miR-138-5p和MACF1相互作用及其机制的影响；(3)Antagomir-138-5p对上述力学去负荷效应的挽救及机制。为深入理解力学去负荷抑制骨形成的力生物学机制提供新的实验依据，并为骨代谢等疾病的防治提供理论基础。

Mechanical stimulus is essential for bone development and growth. Reduction or absence of mechanical stimulus inhibits bone formation and results in bone loss. MicroRNA, as one research hotspot of mechanobiology field, is involved in the regulation of gene expression controlled by mechanical stimulus. Our recent advances showed that miR-138-5p is sensitive to mechanical unloading and negatively regulates bone formation. Besides, MACF1, functioning as one target of miR-138-5p, promotes osteoblast differentiation. Therefore, we propose that miR-138-5p may function as a mechanical-sensitive microRNA and play a key role in mechanical unloading inhibiting bone formation through regulating MACF1 expression. Present project will adopt mechanical unloading models by using random positioning machine in vitro and mouse hindlimb-unloading in vivo, further investigate the following content: (1) The effects of mechanical unloading on bone formation, expression of miR-138-5p and MACF1, and Wnt/β-catenin signaling transduction; (2) The effects of mechanical unloading on the interaction of miR-138-5p and MACF1 and the possible mechanism; (3) The rescue effects of antagomir-138-5p on the above mechanobiological effects and the possible mechanism. The objective of this project is to provide some new experimental evidence for deeply understanding the mechano-biological mechanism of mechanical unloading inhibiting bone formation and also to provide some theoretical basis for prevention and therapy of bone metabolic related diseases.