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

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.