Deficiency of Estrogen Receptor 2 Expression Enhances Disorganization of the Mouse Uterus With Age

Constitutive stimulation of estrogen signaling in mice causes dilated uterine glands with activation of epithelial cell proliferation. In estrogen receptor β knockout (Esr2 KO) mice, cell proliferation in the uterine epithelium is permanently stimulated; therefore, we histologically analyzed the uterine structure in Esr2 KO mice with age. In the uterus of Esr2 KO mice, dilation of the uterine glands was accelerated and the collagen was accumulated in the stroma. The uterine glands were dilated with age even in wild-type (WT) mice; however, Esr2 KO accelerated the dilation of uterine glands quantitatively. The expression of FOXA2 transcription factor, which is essential for uterine glandular function, was diminished in dilated uterine glands of WT and Esr2 KO mice and decreased in the uterine glands of normal size in 12-month-old Esr2 KO mice. To investigate mechanisms of the collagen accumulation in the Esr2 KO uterus, we focused on collagen synthesis and degradation. In the uterine stroma of Esr2 KO mice, MMP8 expression in whole uteri and the number of MMP8-expressing macrophages were decreased. An analysis of the comprehensive gene expression suggested that increased expression of fibroblast growth factors and decreased expression of an aquaporin may be related to the dilation of uterine glands in Esr2 KO mice, and reduced infiltration or differentiation into the macrophages with MMP8 expression may be involved with the collagen accumulation in Esr2 KO mice with age. Taken together, the absence of ESR2 constitutively disrupts estrogen signaling and promotes aging in the uterus via stimulation of epithelial cell proliferation and a decrease of MMP8-expressing macrophages.