BACKGROUND During the human menstrual cycle and pregnancy, the endometrium undergoes a series of dynamic remodeling processes to adapt to physiological changes. Insufficient endometrial remodeling, characterized by inadequate endometrial proliferation, decidualization and spiral artery remodeling, is associated with infertility, endometriosis, dysfunctional uterine bleeding, and pregnancy-related complications such as preeclampsia and miscarriage. Bone morphogenetic proteins (BMPs), a subset of the transforming growth factor-β (TGF-β) superfamily, are multifunctional cytokines that regulate diverse cellular activities, such as differentiation, proliferation, apoptosis, and extracellular matrix synthesis, are now understood as integral to multiple reproductive processes in women. Investigations using human biological samples have shown that BMPs are essential for regulating human endometrial remodeling processes, including endometrial proliferation and decidualization. OBJECTIVE AND RATIONALE This review summarizes our current knowledge on the known pathophysiological roles of BMPs and their underlying molecular mechanisms in regulating human endometrial proliferation and decidualization, with the goal of promoting the development of innovative strategies for diagnosing, treating and preventing infertility and adverse pregnancy complications associated with dysregulated human endometrial remodeling. SEARCH METHODS A literature search for original articles published up to June 2023 was conducted in the PubMed, MEDLINE, and Google Scholar databases, identifying studies on the roles of BMPs in endometrial remodeling during the human menstrual cycle and pregnancy. Articles identified were restricted to English language full-text papers. OUTCOMES BMP ligands and receptors and their transduction molecules are expressed in the endometrium and at the maternal–fetal interface. Along with emerging technologies such as tissue microarrays, 3D organoid cultures and advanced single-cell transcriptomics, and given the clinical availability of recombinant human proteins and ongoing pharmaceutical development, it is now clear that BMPs exert multiple roles in regulating human endometrial remodeling and that these biomolecules (and their receptors) can be targeted for diagnostic and therapeutic purposes. Moreover, dysregulation of these ligands, their receptors, or signaling determinants can impact endometrial remodeling, contributing to infertility or pregnancy-related complications (e.g. preeclampsia and miscarriage). WIDER IMPLICATIONS Although further clinical trials are needed, recent advancements in the development of recombinant BMP ligands, synthetic BMP inhibitors, receptor antagonists, BMP ligand sequestration tools, and gene therapies have underscored the BMPs as candidate diagnostic biomarkers and positioned the BMP signaling pathway as a promising therapeutic target for addressing infertility and pregnancy complications related to dysregulated human endometrial remodeling.

中文翻译：

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骨形态发生蛋白在人类月经周期和妊娠期间子宫内膜重塑中的作用


背景 在人类的月经周期和怀孕过程中，子宫内膜经历一系列动态重塑过程以适应生理变化。子宫内膜重塑不足，以子宫内膜增殖不足、蜕膜化和螺旋动脉重塑为特征，与不孕症、子宫内膜异位症、功能失调性子宫出血以及子痫前期和流产等妊娠相关并发症有关。骨形态发生蛋白 （BMP） 是转化生长因子-β （TGF-β） 超家族的一个子集，是调节多种细胞活动（如分化、增殖、凋亡和细胞外基质合成）的多功能细胞因子，现在被理解为女性多种生殖过程不可或缺的一部分。使用人类生物样本的研究表明，BMP 对于调节人类子宫内膜重塑过程至关重要，包括子宫内膜增殖和蜕膜化。客观和基本原理 本文总结了我们目前关于 BMP 的已知病理生理作用及其在调节人子宫内膜增殖和蜕膜化中的潜在分子机制的知识，目的是促进诊断、治疗和预防与人子宫内膜重塑失调相关的不孕症和不良妊娠并发症的创新策略的发展。检索方法 在 PubMed、MEDLINE 和 Google Scholar 数据库中对截至 2023 年 6 月发表的原始文章进行了文献检索，确定了 BMP 在人类月经周期和怀孕期间子宫内膜重塑中的作用的研究。确定的文章仅限于英文全文论文。 结果 BMP 配体和受体及其转导分子在子宫内膜和母胎界面表达。随着组织微阵列、3D 类器官培养和先进的单细胞转录组学等新兴技术的发展，以及重组人类蛋白质的临床可用性和正在进行的药物开发，现在很明显 BMP 在调节人类子宫内膜重塑方面发挥着多种作用，并且这些生物分子（及其受体）可以靶向诊断和治疗目的。此外，这些配体、其受体或信号决定因素的失调会影响子宫内膜重塑，导致不孕或妊娠相关并发症（例如 子痫前期和流产）。更广泛的影响尽管需要进一步的临床试验，但重组 BMP 配体、合成 BMP 抑制剂、受体拮抗剂、BMP 配体隔离工具和基因疗法开发的最新进展强调了 BMP 作为候选诊断生物标志物，并将 BMP 信号通路定位为解决与失调人类子宫内膜重塑相关的不孕症和妊娠并发症的有前途的治疗靶点。