Bone Morphogenetic Protein 2 Promotes Human Trophoblast Cell Invasion by Inducing Activin A Production

Abstract

Bone morphogenetic protein (BMP) 2 and activin A belong to the TGF-β superfamily and are highly expressed in human endometrium and placenta. Studies have demonstrated that activin A and BMP2 play essential roles in the process of early embryo implantation by promoting human trophoblast cell invasion. However, whether activin A production can be regulated by BMP2 in human trophoblast cells remains unknown. The aim of our study was to determine the effects of BMP2 on activin A production and its role in human trophoblast invasion. Primary human extravillous trophoblast (EVT) cells were used as study models. BMP2 treatment significantly increased inhibin βA (INHBA) mRNA levels and activin A production without altering inhibin α and inhibin βB levels. BMP2-induced EVT cell invasion was attenuated by knockdown of INHBA. The increased INHBA transcription and activin A production by BMP2 were blocked by the type I receptor activin receptor (ACVR)-like kinase 2 (ALK2) and activin receptor-like kinase 3 (ALK3) inhibitor dorsomorphin homolog 1 (DMH-1). BMP2-induced INHBA upregulation was also inhibited by knockdown of type I receptor ALK3 or combined knockdown of type II receptors for BMP2 (BMPR2) and ACVR2A. Whereas BMP2 initiated both canonical SMAD1/5/8 and noncanonical SMAD2/3 signaling, only knockdown of SMAD4, but not SMAD2 and SMAD3, abolished the effects of BMP2 on INHBA. Our results show that BMP2 increases human trophoblast invasion by upregulating INHBA and activin A production via ALK3-BMPR2/ACVR2A-SMAD1/5/8-SMAD4 signaling.

Bone morphogenetic protein 2 promotes human trophoblast cell invasion and endothelial‐like tube formation through ID1‐mediated upregulation of IGF binding protein‐3

“…We have previously shown that BMP2 promotes human trophoblast invasion by upregulating N-cadherin expression and activin A production. 14,15 Here we further demonstrate that ID1 is involved in BMP2-induced trophoblast invasion. However, others have shown that Id1 is downregulated during the differentiation of rat Rcho-1 choriocarcinoma cells into trophoblast giant cells, which are thought to be somewhat equivalent to human EVTs.…”

“…13 Expressed at the maternal-fetal interface, BMP2 plays essential roles in endometrial decidualization and EVT cell invasion. [14][15][16] In addition, embryo implantation promotes endometrium decidualization. 17,18 BMP2 secreted by endometrial cells and trophoblast cells may mediate their cooperation during placentation in an autocrine/paracrine manner.…”

Fractalkine Regulates HEC-1A/JEG-3 Interaction by Influencing the Expression of Implantation-Related Genes in an In Vitro Co-Culture Model

“…BMP2 is a regulator of SMAD2/3 signalling, influencing the effect of activin receptors, and contributing to increased invasiveness [35,62]. BMP2 induces activin production as well, thus increases the activity of activin receptors [69]. In our experiments, BMP2 mRNA expression was significantly higher during the whole experiment compared to the control.…”

The TGFβ Family in Human Placental Development at the Fetal-Maternal Interface

“…BMP2 and activin A are expressed in the human endometrium and placenta. BMP2 induces human TB cell invasion by upregulating activin A and inhibin A. BMP2 initiates both canonical SMAD1/5/8 via the ALK3 receptor and non-canonical SMAD2/3 pathways [46]. The same group extended these studies and showed that BMP2 promotes TB cell invasion by upregulating N-cadherin via non-canonical ALK2/3/4-SMAD2/3-SMAD4 signaling [78].…”