Polymerization of insulin-like growth factor-binding protein-1 (IGFBP-1) potentiates IGF-I actions in placenta

Abstract

Insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1), the main secretory protein of decidua that binds to IGFs and has been shown to inhibit or stimulate IGFs' bioactivities. Polymerization, one of the posttranslational modifications of IGFBP-1, has been shown to lead to loss of inhibiting effect of IGFBP-1 on IGF-I actions. The current studies were undertaken to elucidate the effects of steroid hormones on IGFBP-1 polymerization in trophoblast cell cultures. Placental tissues were obtained during legal, elective procedures of termination of pregnancy performed between 7 and 10 weeks of gestation, and primary trophoblast cells were separated. IGFBP-1 polymerization was analyzed by SDS-PAGE and immunoblotting. IGFBP-1 was polymerized when IGFBP-1 was added to trophoblast cell cultures. Polymerization of IGFBP-1 was inhibited by the addition of anti-tissue transglutaminase antibody into the culture media. There was an increase in the intensity of polymerized IGFBP-1 bands with the addition of medroxyprogesterone acetate (MPA), while no such difference was observed upon treatment with estradiol. MPA also increased the expression of tissue transglutaminase on trophoblast cell membranes. IGF-I stimulated trophoblast cell migration, while IGFBP-1 inhibited this IGF-I-induced trophoblast response. Addition of MPA attenuated the inhibitory effects of IGFBP-1 on IGF-I-induced trophoblast cell migration. IGFBP-1 was polymerized by tissue transglutaminase on the cell surface of trophoblasts, and MPA increased tissue transglutaminase expression on the cell surface and facilitated IGFBP-1 polymerization. These results suggest that progesterone might facilitate polymerization of decidua-secreted IGFBP-1 and increase IGF-I actions at feto-maternal interface, thereby stimulating trophoblast invasion of maternal uterus.