胎源性骨质疏松症的宫内RAS编程机制及早期治疗靶标

As a typical metabolic disease, osteoporosis has a fetal origin, however, the underlying mechanism remains unclear and the early clinical diagnosis and prevention are also limited. It is known that the local bone renin-angiotensin system (RAS) is chronically activated in osteoporosis, and the activated RAS is also associated with the disorder of vascularization of ossification center mediated by osteogenic differentiation. We have previously found that prenatal xenobiotics exposure cause fetal over-exposure to maternal glucocorticoids (GC), impairs bone development and increases the susceptibilities to osteoporosis in adult offspring. The mechanism may be attributed to hypomethylation and overexpression of angiotensin I-converting enzyme (ACE) in bone mesenchymal stem cells (BMSCs) during the directional differentiation of osteogenesis. Therefore, this project aims to investigate the potential interactions among a series of events basing on the models of both animal and BMSCs, including “intrauterine high level of maternal GC - GR/Sp1 overexpression - ACE hypomethylation and enhanced expression-suppressed osteogenic differentiation of BMSCs related to AT2R - impaired bone development and increased susceptibility to adult osteoporosis”. Meanwhile, the intrauterine programming mechanism of osteoporosis mediated by fetal over-exposure to maternal GC could be elucidated. The role of ACE as a target for early intervention of fetal originated osteoporosis will be validated. This study is of great theoretical and practical significance for guiding prenatal and postnatal care and improving quality of life.

骨质疏松症属于代谢性疾病，具有胎儿起源，但其发生机制不明，临床早期诊治困难。已知成年骨质疏松症患者的骨量减少并伴有骨肾素-血管紧张素系统（RAS）慢性激活。本室前期研究发现，孕期外源物暴露所致宫内发育迟缓胎儿母源性糖皮质激素（GC）过暴露、骨发育不良及骨质疏松症易感。其机制可能与骨髓间充质干细胞（BMSCs）成骨定向分化过程中的血管紧张素转换酶（ACE）启动子区低甲基化及高表达有关。本项目拟在前期研究基础上，在整体和细胞水平，探讨“高GC—GR/Sp1高表达—ACE启动子表遗传修饰异常及高表达—AT2R相关成骨细胞分化抑制—骨发育不良及成年骨质疏松症易感性增加”之间的内在联系，阐明母源性高GC诱导胎儿骨质疏松症易感的宫内RAS编程机制，确证ACE为胎源性骨质疏松症的早期干预靶标。本项目实施对于贯彻优生优育国策和早期防治胎源性骨质疏松症的发生，具有重要理论和现实意义。

骨质疏松症属于代谢性疾病，具有胎儿起源，但其发生机制不明，临床早期诊治困难。本项目建立了四种孕期外源物(咖啡因、乙醇、尼古丁和地塞米松)暴露的大鼠模型，证实了孕期外源物暴露可引起子代大鼠宫内发育迟缓及长骨发育不良，并在出生后早期及成年期出现骨量低下以及骨质疏松症表现。为此，本项目基于动物模型充分解析了骨质疏松症的胎儿起源现象。进一步，本项目阐明了胎源性骨质疏松症的宫内肾素-血管紧张素系统(RAS)的表观遗传编程机制，包括DNA甲基化与组蛋白乙酰化修饰机制，并证实了其宫内RAS表观遗传编程改变与糖皮质激素的间接编程和外源物的直接作用有关。其中，孕期外源物暴露(如咖啡因)可致胎儿血糖皮质激素升高，后者可持续下调血管紧张素转化酶(ACE)基因启动子区的甲基化水平，引起骨局部ACE表达持续上调及RAS激活，从而导致成骨分化抑制和骨量低下，即糖皮质激素间接编程机制；然而，孕期外源物暴露(如乙醇、尼古丁和地塞米松)可直接上调ACE基因启动子区组蛋白乙酰化水平(H3K9ac、H3K27ac)，导致ACE表达持续上调及RAS激活，引起成骨分化抑制和骨量低下，即外源物的直接作用机制。基于此，本项目提出了ACE是孕期外源物暴露所致胎源性骨质疏松症发生的早期干预靶标，并在整体动物水平进行骨靶向干预ACE后发现可有效改善胎源性骨质疏松症发生。此外，在本项目在原有的研究内容上发现了，孕期咖啡因暴露所致的子代大鼠长骨发育不良及骨质疏松症易感存在性别差异，主要体现在雄性子代较雌性子代骨发育毒性更重且骨质疏松症更为易感，并且阐明了以11β-羟基类固醇脱氢酶2 (11β-HSD2)性别差异性表达有关的发生机制。同时，我们也发现孕期外源物(咖啡因和地塞米松)暴露所致的子代软骨下骨骨质疏松性改变与骨关节炎发生密切相关，并创新性揭示了软骨下骨骨质疏松的胎儿发育起源现象。本项目对于贯彻优生优育国策和早期防治胎源性骨质疏松症发生，具有重要理论和现实意义。