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Follistatin-Related Gene (FLRG) Expression in Human Endometrium: Sex Steroid Hormones Regulate the Expression of FLRG in Cultured Human Endometrial Stromal Cells

Department of Obstetrics and Gynecology (H.-Q.W., K.Ta., Y.N.) and Molecular Neuroscience Research Center, (M.N.), Otsu 520-2192, Shiga, Japan; and Institute for Enzyme Research, University of Tokushima (K.Ts.), Kuramoto, Tokushima, 770-8503 Japan

Address all correspondence and requests for reprints to: Koichi Takebayashi, M.D., Department of Obstetrics and Gynecology, Shiga University of Medical Science, Seta, Tsukinowa-cho, Otsu 520-2192, Japan. E-mail: ktakebay{at}belle.shiga-med.ac.jp.

Follistatin-related gene (FLRG) encodes a novel secreted glycoprotein that is highly homologous to follistatin and binds activins and bone morphogenetic proteins, members of the TGFß superfamily of growth/differentiation factors. FLRG protein inhibits activin-induced and bone morphogenetic protein-2-induced transcriptional responses in a dose-dependent manner, and its mRNA is abundantly expressed in human placenta, heart, aorta, testis, and adrenal gland. In this study we showed that FLRG mRNA was expressed in human endometrium across the menstrual cycle and in decidua of early pregnancy. In the proliferative phase of the menstrual cycle, FLRG protein was detected predominantly in the cytoplasm of endometrial epithelium. In the secretory phase and in early pregnancy, it was also detected in the nuclei of endometrial stromal cells. Using in vitro decidualization model, we demonstrated that 17ß-estradiol plus progesterone, but not 17ß-estradiol or progesterone alone, induced FLRG expression significantly. These results suggest that FLRG expression in endometrial stromal cells is regulated by the concerted action of ovarian steroid hormones via decidualization, and FLRG protein may participate in the regulation of stromal cell decidualization as a binding protein for members of TGFß superfamily.

This work was supported by grants-in-aid from the Ministry of Education, Science, and Culture (Grant 11770937).

Abbreviations: BMP, Bone morphogenetic protein; E₂, 17ß-estradiol; EF-1, elongation factor-1; ESC, endometrial stromal cells; FLRG, follistatin-related gene; P, progesterone; PBS (-), Ca²⁺ and Mg²⁺ free PBS.

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