骨衰老进程中BMNCR基因影响骨髓间充质干细胞归巢与成骨分化的机制研究

The homing of bone marrow mesenchymal stem cells (BMSCs) onto the bone surface and differentiation into osteoblasts is a critical event in bone formation. This process is blocked during bone aging and leads to osteoporosis. Our previous study showed that the expression of LncRNA BMNCR in BMSCs was significantly down-regulated in elderly people and elderly mice, and was related to the function of homing proteins and osteogenic genes. Based on the findings, we propose a scientific hypothesis that the lack of BMNCR gene in the process of bone aging leads to the decrease of the ability of BMSCs to home to bone surface and commitment to osteoblasts, involving in osteoporosis. To test this hypothesis, we will construct BMNCR knockout mice, using stem cell tracing mouse models to observe the effects of BMNCR defects on BMSCs homing and cell fate, as well as bone aging. We will furthermore analyze the interaction network between BMNCR and homing protein / osteogenic transcription factors, and to reveal the intrinsic process of homing- osteogenesis events. We will also observe its therapeutic effect on senile bone loss. This study is helpful to elucidate the mechanism of bone aging and provide a new approach for the prevention and treatment of bone aging.

骨髓间充质干细胞（BMSCs）在骨表面归巢并向成骨细胞分化，是骨形成的关键事件，骨衰老时这一进程受阻，导致骨质疏松。我们前期研究发现老年人群及老年小鼠BMSCs长链非编码RNA基因BMNCR表达明显下调，并与归巢蛋白及成骨基因功能相关，因此，我们提出“骨衰老进程中BMNCR基因缺乏，致BMSCs在骨表面归巢与成骨分化减少，参与骨质疏松发生”这一科学假说。为了验证这一假说，本课题构建BMNCR基因敲除小鼠，利用干细胞示踪小鼠模型，观察BMNCR缺陷对BMSCs归巢与命运转归以及骨衰老的影响。解析BMNCR与归巢蛋白/成骨转录因子之间的的作用网络，揭示归巢-成骨事件的内在程序。并观察其对老年性骨丢失的治疗作用。本研究有助于阐明骨衰老机理，为其防治提供新途径。

骨髓间充质干细胞（BMSCs）在骨表面归巢并向成骨细胞分化，是骨形成的关键事件，骨衰老时这一进程受阻，导致骨质疏松。本课题解析BMNCR与归巢蛋白/成骨转录因子之间的的作用网络，揭示归巢-成骨事件的内在程序。本课题通过构建BMNCR基因敲除小鼠，利用干细胞示踪小鼠模型，观察BMNCR缺陷对BMSCs归巢与命运转归以及骨衰老的影响，阐明Bmncr通过作用于纤调蛋白FMOD以及BMP2信号通路调节BMSCs成骨微环境，并发现Bmncr可以通过联接TAZ与ABL形成复合体调控BMSCs成骨-成脂分化偏移，上述研究成果发表在J Clin Invest, 2018。同时本课题发现lncRNA-Hnscr通过直接延缓下丘脑神经干细胞（htNSCs）衰竭，从而延缓整个机体的衰老进程，鉴定出茶叶提取物茶黄素theaflavin 3-gallate可通过模拟Hnscr功能，延缓机体衰老，上述研究成果发表在Cell Metabolism，2020。本课题还发现特异性抑制脂肪组织中miR-188水平能够显著改善衰老相关的脂肪代谢紊乱表型，上述研究成果发表在Aging Cell, 2020。