雌激素缺乏诱发骨质疏松的新机制-lncRNA

Osteoporosis is a common occurring disease in postmenopausal women. A large number of studies have demonstrated that estrogen deficiency is the most important pathological factor of occurrence of osteoporosis in postmenopausal women, but the molecular mechanism of estrogen deficiency-induced osteoporosis has not yet fully understood. It is necessary to explore the detailed mechanisms and look for the new target for estrogen deficiency-induced osteoporosis. Latest study found that long non-coding RNAs (lncRNAs) are closely related to the occurrence of many diseases. We found for the first time that the lncRNA-e2diopl was associated with osteoporosis in ovariectomized mice, but its mechanisms remains unclear. In this project we will study the following contents: (1) reveal the relationship between e2diopl and estrogen deficiency-induced osteoporosis, and elucidate the molecular mechanism of e2diopl regulation of osteoporosis; (2) identify the e2diopl as a therapeutic target of estrogen deficiency-induced osteoporosis, and provide new thoughts for the treatment of osteoporosis in postmenopausal women; (3) detect the expression of e2diopl in peripheral blood of ovariectomized mice and postmenopausal women with osteoporosis, and investigate whether e2diopl can predict the occurrence of postmenopausal osteoporosis.

骨质疏松是绝经后女性的常见病，大量研究证实雌激素缺乏是女性骨质疏松发生的最关键因素，但是雌激素缺乏诱发骨质疏松的分子机制尚未完全阐明，因此探索雌激素缺乏诱发骨质疏松的深层机制、寻找骨质疏松防治的新靶点具有重要科学意义。最新研究发现长链非编码RNAs（lncRNAs）与多种疾病的发生密切相关。在前期实验中我们在去卵巢小鼠骨组织中发现一个与骨质疏松发生相关的lncRNA—e2diopl，但其分子机制有待阐明。在本项目中我们将研究以下三方面内容：（1）揭示e2diopl与雌激素缺乏诱发骨质疏松之间的关系，阐明e2diopl调控骨质疏松发生的信号通路；（2）明确以e2diopl为调控靶点是否可以治疗雌激素缺乏诱发的骨质疏松，进而为绝经后女性骨质疏松治疗提供新思路；（3）检测e2diopl在去卵巢小鼠和临床绝经后骨质疏松患者外周血中的表达，探讨e2diopl是否可以成为绝经后骨质疏松的预警因子。

骨髓间充质干细胞具有分化为成骨细胞或脂肪细胞的潜力，成骨和成脂分化之间的转变决定了骨质量。骨髓脂肪增多可能是导致骨质疏松发病的主要原因之一。LncRNAs参与调控多种疾病的病理生理过程，但在骨代谢调控和骨质疏松中的作用尚未完全阐明，本项目亦在探讨lncRNA-ORLNC1是否通过改变骨髓间充质干细胞的成骨/成脂肪分化平衡参与骨质疏松的调控及其分子机制。应用一系列实验手段我们发现（1）雌激素剥夺诱导的骨质疏松小鼠骨组织、骨髓间充质干细胞及骨质疏松病人血清中lncRNA-ORLNC1表达水平显著增加，而miR-296表达水平显著降低;（2）过表达lncRNA-ORLNC1抑制骨髓间充干细胞向成骨分化，促进其向脂肪分化，因而促进骨丢失和骨质疏松症的发生，并恶化骨质疏松小鼠的表型; 然后抑制lncRNA-OR;NC1的表达可以显著促进骨髓间充质干细胞向成骨分化，并改善骨质疏松小鼠的表型;（3）骨髓间充质细胞向成骨分化时miR-296表达水平显著增加，并且过表达miR-296通过靶向抑制下游蛋白Pten表达水平蛋白促进骨髓间充质干细胞的成骨分化，抑制其向成脂分化;（4）lncRNA-ORLNC1作为miR-296的ceRNA抑制其活力，间接增加Pten蛋白表达水平，继而破坏骨髓间充质干细胞的成骨分化能力，是雌激素诱导骨质疏松发生的新的重要调控分子机制。本项目为抗骨质疏松症的药物研发提供理论基础和实验性依据，对于绝境后妇女骨质疏松的防治具有重要的科学意义和临床应用价值。