BMP2/LOX通路在多囊卵巢综合征排卵障碍中的作用机制研究

Polycystic ovary syndrome (PCOS) is a common endocrine disorder and metabolic disease, which severely affects women fertility. However, the pathogenesis of PCOS is still unknown. Previous study demonstrated that bone morphogenetic protein 2 (BMP2) expression levels in PCOS granulosa cells were higher than non-PCOS and BMP2 induced the upregulation of lysyl oxidase (LOX) expression levels in human granulosa cells. LOX is a catalytic enzyme responsible for ovulation by regulating extracellular matrix remodeling. The aberrant overexpression of LOX was present in PCOS granulosa cells and LOX activity in follicular fluid was also higher compared with non-PCOS patients. The inhibition of LOX expression ameliorated anovulation in PCOS. Therefore, we hypothesized that the aberrant expression of BMP2 might induce the LOX expression in PCOS granulosa cells and then led to the PCOS anovulation. Here, PCOS clinic sample and mouse were utilized as the research model to explore the role of BMP2/LOX pathway in PCOS anovulation and underlying molecular mechanism. This study will discover the new mechanism of BMP2/LOX pathway in PCOS anovulation and provide the new insight and theoretical basis for pathogenesis of PCOS anovulation and target treatment.

多囊卵巢综合征（PCOS）是一类严重影响育龄女性生育能力的内分泌代谢性疾病，其发病机制不清晰。研究发现，PCOS患者卵巢颗粒细胞中的骨形态发生蛋白2（BMP2）表达水平高于非PCOS患者，且BMP2可以正向调控PCOS排卵障碍相关基因赖氨酰氧化酶（LOX）的表达。LOX是排卵过程中卵泡内细胞外基质重塑的催化酶，PCOS患者颗粒细胞中LOX的表达出现异常升高，抑制LOX的表达可以改善PCOS排卵异常的症状。由此推测，BMP2可能通过上调LOX的表达参与PCOS排卵障碍的发生。因此，本项目将以PCOS临床样本和小鼠为研究对象，探讨BMP2/LOX通路在PCOS排卵障碍发生中的作用及潜在分子机制。本研究将揭示BMP2/LOX通路调控PCOS排卵障碍的新机制，为研究PCOS排卵障碍的发病机理以及针对性治疗提供新的思路和理论基础。

多囊卵巢综合征（polycystic ovary syndrome, PCOS）是一类严重影响育龄女性生育能力的内分泌代谢性疾病，其病因复杂且发病机制至今未明。前期研究证明，骨形态发生蛋白2（bone morphogenetic protein 2, BMP2）和赖氨酰氧化酶（lysyl oxidase, LOX）可能参与PCOS的发生，且BMP2调控LOX的表达。因此，本项目围绕BMP2/LOX通路在PCOS排卵障碍中的作用及调控机制开展研究，以PCOS患者临床样本和小鼠模型为研究对象，深入探讨了BMP2/LOX通路在PCOS发生过程中的作用以及分子调控机制。通过本项目的研究，发现了PCOS患者颗粒细胞BMP2表达水平上升，卵泡液中BMP2表达水平和LOX的含量呈正相关性。动物模型实验结果表明，注射BMP2重组蛋白引起小鼠发情周期紊乱。然而，注射BMP2蛋白受体抑制剂SB-431542，可显著缓解DHEA诱导的PCOS表型。BMP2通过上调SNAIL蛋白的表达从而促进人颗粒细胞中LOX表达水平上升。同时，发现了BMP2可以上调排卵相关基因透明质酸合成酶（hyaluronan synthase, HAS2）的表达从而促进透明质酸的合成，而结缔组织生长因子（connective tissue growth factor, CTGF）是BMP2诱导人颗粒细胞中透明质酸合成的调控因子。最后，本项目证明了BMP2可以通过SMAD4促进人颗粒细胞中CTGF、HAS2表达以及透明质酸的合成。本项目研究结果明确了BMP2/LOX通路在PCOS发生过程中的作用，解析了其引起PCOS发生的致病机制，为PCOS患者的临床诊疗提供了新的思路。