BMP7 Induces Uterine Receptivity and Blastocyst Attachment

Abstract

In women, the window of implantation is limited to a brief 2- to 3-day period characterized by optimal levels of circulating ovarian hormones and a receptive endometrium. Although the window of implantation is assumed to occur 8 to 10 days after ovulation in women, molecular markers of endometrial receptivity are necessary to determine optimal timing prior to embryo transfer. Previous studies showed that members of the bone morphogenetic protein (BMP) family are expressed in the uterus necessary for female fertility; however, the role of BMP7 during implantation and in late gestation is not known. To determine the contribution of BMP7 to female fertility, we generated Bmp7flox/flox-Pgr-cre+/- [BMP7 conditional knockout (cKO)] mice. We found that absence of BMP7 in the female reproductive tract resulted in subfertility due to uterine defects. At the time of implantation, BMP7 cKO females displayed a nonreceptive endometrium with elevated estrogen-dependent signaling. These implantation-related defects also affected decidualization and resulted in decreased expression of decidual cell markers such as Wnt4, Cox2, Ereg, and Bmp2. We also observed placental abnormalities in pregnant Bmp7 cKO mice, including excessive parietal trophoblast giant cells and absence of a mature placenta at 10.5 days post coitum. To establish possible redundant roles of BMP5 and BMP7 during pregnancy, we generated double BMP5 knockout/BMP7 cKO [BMP5/7 double knockout (DKO)] mice; however, we found that the combined deletion had no additive disruptive effect on fertility. Our studies indicate that BMP7 is an important factor during the process of implantation that contributes to healthy embryonic development.

Role of Transforming Growth Factor β in Uterine Fibroid Biology

“…BMPs play a vital role in bone and cartilage development. These proteins are involved in the TGF-β signaling pathway and in cytokine receptor interaction [ 69 ], and are one of the proteins that are responsible for endometrial receptivity, e.g., BMP-2 and BMP-7 [ 70 , 71 ]. TGF-β3 decreases human endometrium receptivity by decreasing the expression of BMP receptors [ 65 ].…”

TGFβ superfamily signaling and uterine decidualization

“…Unlike BMP2, BMP7 reduces E2/P4-induced expression of IGFBP1 mRNA in human ESCs in culture, suggesting an inhibitory role of BMP7 in ESC decidualization [ 76 ]. This finding seems to contradict results from the mouse model in which loss of BMP7 affects decidual gene expression [ 52 ]. Expression analysis has shown that the levels of BMPR1A, BMPR1B and BMPR2 are lower in leiomyoma-associated endometrium that secretes high levels of TGFβ3 versus normal endometrium [ 77 ].…”

“…Loss of BMP2 in the uterus renders the mouse infertile and the uterus is unable to decidualize, owing to the dysregulation of multiple genes including Wnt4/6 , FK-506 binding proteins ( Fkbps ), and prostaglandin synthase2 ( Ptgs2 ) [ 41 ]. Recently, conditional deletion of Bmp7 induces implantation defects and dysregulation of decidual genes including Bmp2 , Ptgs2 , Wnt4 , and epiregulin ( Ereg ) [ 52 ]. However, Bmp7 cKO mice respond normally to artificial decidualization stimuli [ 52 ].…”

“…Recently, conditional deletion of Bmp7 induces implantation defects and dysregulation of decidual genes including Bmp2 , Ptgs2 , Wnt4 , and epiregulin ( Ereg ) [ 52 ]. However, Bmp7 cKO mice respond normally to artificial decidualization stimuli [ 52 ]. Results of in vitro culture studies using undifferentiated uterine stromal cells from pregnant mice reinforce the role of BMP2-WNT4 signaling in decidualization [ 53 ].…”

A Potential Role of Bone Morphogenetic Protein 7 in Shell Formation and Growth in the Razor Clam Sinonovacula constricta

“…BMP7 has also been shown to play significant roles in the development of various types of tissues, such as kidney and brown adipose tissue. In mice, BMP7 was involved in sertoli cell proliferation during early postnatal development, and BMP 7 gene knockout mice caused infertility ( Puglisi et al, 2004 ; Monsivais et al, 2017 ). BMP7 has also been shown to participate in embryogenesis, tissue growth, and neurogenesis ( Bragdon et al, 2011 ; Kowtharapu et al, 2018 ).…”