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。

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.