脂肪源性血浆外泌体miRNA在调控破骨细胞功能和绝经后骨质疏松症发病中作用机制和干预策略

Osteoporosis is one of major health challenges for the elderly, especially in postmenopausal women. In-depth investigation of the molecular mechanism of abnormal activation of osteoclast is really important for prevention and treatment of postmenopausal osteoporosis. In our preliminary study, we found that serum FGF21 elevated with ovariectomy in mice, complicated with decreased circulating exosomal miRNA expression which could inhibit FGF21. FGF21 could stimulate osteoclast differentiation and activation, and recent study has verified that adipose tissue is an important source of circulating exosomal miRNAs. These results suggest that adipose-derived circulating exosomal miRNA might regulate osteoclast differentiation and activation via FGF21, and may be involved in postmenopausal osteoporosis, however, the role and underlying mechanism is still unclear. In this project, we will try to investigate the role of adipose-derived circulating exosomal miRNA in regulating FGF21, bone metabolism and osteoclast differentiation and activation by inhibiting miRNA expression in adipose tissue through conditional knockout approach; To identify the above functions are mediated by FGF21 signaling through silencing FGF21 expression in liver; To explore the role and mechanism of adipose-derived circulating exosomal miRNA in the pathogenesis of postmenopausal osteoporosis, and test the intervention strategy by investigating the effect of estrogen in regulating adipose-derived circulating exosomal miRNA expression. This project will not only illuminate the underlying mechanism of postmenopausal osteoporosis, but also provide new thoughts for prevention and treatment of this disease.

骨质疏松症严重危害老年人健康，其对绝经后女性的危害性尤为显著。深入研究绝经后骨质疏松症（PMO）的启动因素（破骨细胞异常活化）的分子机制，对该病的防治具有重要意义。我们前期研究发现：卵巢切除后小鼠血浆FGF21水平升高，伴随抑制FGF21的血浆外泌体miRNA表达下调。FGF21可显著促进破骨细胞活化，且最新研究证实脂肪组织是血浆外泌体miRNA的重要来源。这些结果提示：脂肪源性血浆外泌体miRNA可能通过FGF21调控破骨细胞分化，与PMO发病相关，但作用机制尚不明确。本项目通过条件性基因敲除技术阻断脂肪源性miRNA表达，研究其对骨代谢及破骨细胞活化的作用；通过沉默肝脏FGF21表达，验证上述作用是否经由FGF21途径介导；分析脂肪源性血浆外泌体miRNA受雌激素的调控作用，探讨其在PMO发病中的作用机制及干预策略。本项目不仅有助于揭示PMO的发病机制，而且有望为该病的防治提供新思路。

骨质疏松症严重危害老年人健康，其对绝经后女性的危害性尤为显著。深入研究绝经后骨质疏松症（PMO）的启动因素（破骨细胞异常活化）的分子机制，对该病的防治具有重要意义。雌激素缺乏导致小鼠骨质疏松的同时，血浆外泌体中miRNAs表达谱发生显著变化。其中miR-34a和miR-99b表达差异最为显著。通过靶点基因预测发现miR-99b可能的靶基因是FGF21，血浆FGF21水平检测也证实随着卵巢切除后miR-99b水平下降，FGF21水平显著增加。而且FGF21下游基因IGFBP1水平也随之增加。卵巢切除小鼠补充miR-99b后可以显著降低FGF21，IGFBP1水平，抑制雌激素缺乏诱导的骨质疏松和破骨细胞异常活化。总之，雌激素缺乏可能通过miR-99b/FGF21/IGFBP1调控骨代谢，导致破骨细胞异常活化。