Osteopontin Is Expressed in the Mouse Uterus during Early Pregnancy and Promotes Mouse Blastocyst Attachment and Invasion In Vitro

Abstract

Embryo implantation into the maternal uterus is a decisive step for successful mammalian pregnancy. Osteopontin (OPN) is a member of the small integrin-binding ligand N-linked glycoprotein family and participates in cell adhesion and invasion. In this study, we showed that Opn mRNA levels are up-regulated in the mouse uterus on day 4 and at the implantation sites on days 5 and 8 of pregnancy. Immunohistochemistry localized the OPN protein to the glandular epithelium on day 4 and to the decidual zone on day 8 of pregnancy. OPN mRNA and proteins are induced by in vivo and in vitro decidualization. OPN expression in the endometrial stromal cells is regulated by progesterone, a key regulator during decidualization. As a secreted protein, the protein level of OPN in the uterine cavity is enriched on day 4, and in vitro embryo culturing has indicated that OPN can facilitate blastocyst hatching and adhesion. Knockdown of OPN attenuates the adhesion and invasion of blastocysts in mouse endometrial stromal cells by suppressing the expression and enzymatic activity of matrix metalloproteinase-9 in the trophoblast. Our data indicated that OPN expression in the mouse uterus during early pregnancy is essential for blastocyst hatching and adhesion and that the knockdown of OPN in mouse endometrial stroma cells could lead to a restrained in vitro trophoblast invasion.

Role of osteopontin in decidualization and pregnancy success

“…Besides, previous studies also revealed OPN expression in stromal cells is increased at the end of the secretory phase, which is consistent with the time when perivascular stromal cells begin to decidualize (Apparao et al 2001, von Wolff et al 2004. OPN-deficient mice manifested a decreased pregnancy rate during mid-gestation and knockdown of OPN in mouse endometrial stromal cells lead to a restrained trophoblast invasion in vitro (Weintraub et al 2004, Qi et al 2014. Our previous study also proved that OPN is activated in mouse endometrial stromal cells (mESC) and human endometrial stromal cells (hESC) by estrogen (E2) and progesterone (P4) (von Wolff et al 2004, Qi et al 2014.…”

“…OPN-deficient mice manifested a decreased pregnancy rate during mid-gestation and knockdown of OPN in mouse endometrial stromal cells lead to a restrained trophoblast invasion in vitro (Weintraub et al 2004, Qi et al 2014. Our previous study also proved that OPN is activated in mouse endometrial stromal cells (mESC) and human endometrial stromal cells (hESC) by estrogen (E2) and progesterone (P4) (von Wolff et al 2004, Qi et al 2014. These results suggested that OPN plays an important role in regulating blastocyst implantation and decidualization.…”

“…The accumulation of specific cytokines, growth factors, adhesion molecules, as well as immune cells in endometrium is important for uterine receptivity establishment (Zhang et al 2013). OPN is specifically highly expressed in receptive endometrium in humans and mice (Johnson et al 2003, Qi et al 2014, and functional blockade of OPN significantly inhibited implantation (Zhang et al 2013). Previous study reported that endometrial biopsy could improve the pregnancy rate in IVF patients with recurrent implantation failure, the biopsy process may cause the differentiation of monocyte into dendritic cells, by which the OPN and its receptors were induced in endometrial cells, these processes were regarded as molecular mechanism of biopsy-related successful pregnancy (Gnainsky et al 2015).…”

The Multifaceted Actions of Leukaemia Inhibitory Factor in Mediating Uterine Receptivity and Embryo Implantation

“…Reorganization of α3 integrin expression from the apico‐basal‐lateral surface of the LE to expression predominantly at the basal surface was induced by LIF. LIF treatment strongly induces expression of the RGD integrin‐binding ECM protein osteopontin (OPN), . Although OPN −/− mice and human erythroblasts exhibit defects in F‐actin filament organization, its apparent importance in embryo attachment is unclear as SPP1/OPN null mice do not exhibit implantation failure …”

Regulation of Pregnancy: Evidence for Major Roles by the Uterine and Placental Kisspeptin/KISS1R Signaling Systems

“…This conclusion is based on the findings that FOXA2 expression is diminished in rescued glands, and that E2-rescued glands exhibit diminished expression of additional molecules (LIF, SPP1, Prss28, Prss29, Spink3, and Ttr) implicated in gland function. 46,47,[49][50][51][52][53][54] Thus, we concluded that kisspeptin/KISS1R signaling positively regulates both gland development and function.…”