School of Nursing, Hangzhou Medical College, Hangzhou, China.
Department of Obstetrics and Gynaecology, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
FASEB J. 2022 May;36(5):e22319. doi: 10.1096/fj.202200081RR.
Bone morphogenetic protein 2 (BMP2) has been shown to act as a critical regulator in the processes of embryo implantation and endometrial decidualization. The expression and production of pentraxin 3 (PTX3) is essential for successful pregnancy, and aberrant production of PTX3 is involved in the pathogenesis of several vascular complications during pregnancy. Studies have shown that several transforming growth factor β superfamily members, including BMP2, can regulate female reproductive function by modulating the expression of PTX3 in human granulosa cells. However, to date, whether BMP2 can regulate the production of PTX3 during endometrial decidualization remains to be elucidated. In this study, we aimed to explore the effect of BMP2 on the expression and production of PTX3 and the underlying molecular mechanisms using immortalized human endometrial stromal cells (I-HESCs) and human decidual stromal cells (HDSCs). We demonstrated that treatment with exogenous BMP2 significantly suppressed PTX3 production by decreasing the mRNA level of PTX3 in both I-HESCs and HDSCs. The results also showed that BMP2 activated SMAD signaling by inducing an increase in the protein levels of phosphorylated SMAD1/5/8, and this effect could be abolished by pretreatment with the ALK2/3 inhibitor DMH-1 but not with the ALK1/4/7 inhibitor SB431542. Additionally, combined knockdown of ALK2 and ALK3 completely reversed the BMP2-induced suppressive effect on PTX3 expression, while concomitant knockdown of SMAD1 and SMAD5 or knockdown of SMAD4 completely reversed the BMP2-induced suppressive effect on PTX3 expression. Taken together, these results indicate that BMP2 suppressed PTX3 production by decreasing PTX expression, which is mediated by a canonical ALK2/3-mediated SMAD1/5-SMAD4-dependent signaling pathway. Our findings suggest that BMP2 may potentially regulate the process of endometrial decidualization by suppressing the production of PTX3 in humans.
骨形态发生蛋白 2（BMP2）已被证明在胚胎着床和子宫内膜蜕膜化过程中起着关键的调节作用。五聚素 3（PTX3）的表达和产生对于成功怀孕至关重要，而 PTX3 的异常产生与怀孕期间几种血管并发症的发病机制有关。研究表明，包括 BMP2 在内的几种转化生长因子 β 超家族成员可以通过调节人颗粒细胞中 PTX3 的表达来调节女性生殖功能。然而，迄今为止，BMP2 是否可以调节子宫内膜蜕膜化过程中 PTX3 的产生仍有待阐明。在这项研究中，我们旨在使用永生化的人子宫内膜基质细胞（I-HESCs）和人蜕膜基质细胞（HDSCs）来探讨 BMP2 对 PTX3 表达和产生的影响及其潜在的分子机制。我们证明，外源性 BMP2 通过降低 I-HESCs 和 HDSCs 中 PTX3 的 mRNA 水平显著抑制了 PTX3 的产生。结果还表明，BMP2 通过诱导磷酸化 SMAD1/5/8 蛋白水平的增加来激活 SMAD 信号通路，并且该作用可以通过预处理 ALK2/3 抑制剂 DMH-1 而不是 ALK1/4/7 抑制剂 SB431542 来消除。此外，ALK2 和 ALK3 的联合敲低完全逆转了 BMP2 对 PTX3 表达的抑制作用，而 SMAD1 和 SMAD5 的同时敲低或 SMAD4 的敲低完全逆转了 BMP2 对 PTX3 表达的抑制作用。总之，这些结果表明，BMP2 通过降低 PTX 表达来抑制 PTX3 的产生，这是由一个经典的 ALK2/3 介导的 SMAD1/5-SMAD4 依赖的信号通路介导的。我们的研究结果表明，BMP2 可能通过抑制人类 PTX3 的产生来调节子宫内膜蜕膜化过程。
