骨细胞来源的力学敏感lncRNA在骨髓间充质干细胞分化中的作用及机理研究

摘要：机械应力刺激是影响骨组织生长和重建的重要调控因素，骨细胞作为骨组织中的核心力学感受器，可以将力学负荷转换为生物信号来调节成骨细胞和破骨细胞参与骨重建。然而关于应力刺激后骨细胞如何调控骨髓间充质干细胞（BMSCs）分化以及长链非编码RNA（lncRNA）在其中的作用还有待研究。本项目将利用细胞流体剪切力和小鼠活体力学负荷模型探究骨细胞在应力作用下对BMSCs分化的影响，分析力学敏感lncRNA的差异表达，构建lncRNA骨细胞特异性敲除小鼠。通过综合运用loss of function和gain of function细胞生物学和分子生物学手段，在体内和体外研究应力刺激下骨细胞来源的lncRNA调控BMSCs分化的分子机制并分析其对骨骼生物力学以及骨稳态的影响。本研究揭示了骨细胞调控骨重建的新作用方式，为骨细胞生物力学的研究提供新的视角，具有重要的科学创新意义。

The mechanical force applied on bone tissue regulates both bone growth and bone remodeling. As a core mechanoreceptor in bone tissue, osteocytes can translate mechanical forces into biological signals to orchestrate the participation of osteoblasts and osteoclasts in bone remodeling. However, the way of bone marrow mesenchymal stem cells (BMSCs) differentiation governed by osteocytes under mechanical force and the role of long non-coding RNA (lncRNA) are still in need of research. The current proposal will explore the impact of osteocytes under mechanical loading on BMSCs differentiation by using fluid shear stress and the in vivo mouse force loading model, analyze the differential expression of mechano-sensitive lncRNA and generate osteocyte conditional lncRNA knockout mice. It will endeavor to discover the underlying mechanisms of osteocyte-derived lncRNA regulating BMSCs differentiation after mechanical stimulation and affecting bone mechanobiology and homeostasis by virtue of the gain- and loss-of-function. In addition, the proposal provides insight into the regulation mechanism of bone remodeling by osteocytes from a new perspective and significantly contributes to study in osteocyte mechanobiology.