17β-Estradiol (E2) Activates Matrix Mineralization through Genomic/Nongenomic Pathways in MC3T3-E1 Cells

Author:

Suzuki Hiraku12ORCID,Fujiwara Yuki1ORCID,Ariyani Winda1ORCID,Amano Izuki1ORCID,Ishii Sumiyasu1ORCID,Ninomiya Ayane Kate1ORCID,Sato Seiichi23ORCID,Takaoka Akinori23,Koibuchi Noriyuki1ORCID

Affiliation:

1. Department of Integrative Physiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Gunma, Japan

2. Division of Signaling in Cancer and Immunology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Hokkaido, Japan

3. Molecular Medical Biochemistry Unit, Biological Chemistry and Engineering Course, Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0815, Hokkaido, Japan

Abstract

Estrogen plays an important role in osteoporosis prevention. We herein report the possible novel signaling pathway of 17β-estradiol (E2) in the matrix mineralization of MC3T3-E1, an osteoblast-like cell line. In the culture media-containing stripped serum, in which small lipophilic molecules such as steroid hormones including E2 were depleted, matrix mineralization was significantly reduced. However, the E2 treatment induced this. The E2 effects were suppressed by ICI182,780, the estrogen receptor (ER)α, and the ERβ antagonist, as well as their mRNA knockdown, whereas Raloxifene, an inhibitor of estrogen-induced transcription, and G15, a G-protein-coupled estrogen receptor (GPER) 1 inhibitor, had little or no effect. Furthermore, the E2-activated matrix mineralization was disrupted by PMA, a PKC activator, and SB202190, a p38 MAPK inhibitor, but not by wortmannin, a PI3K inhibitor. Matrix mineralization was also induced by the culture media from the E2-stimulated cell culture. This effect was hindered by PMA or heat treatment, but not by SB202190. These results indicate that E2 activates the p38 MAPK pathway via ERs independently from actions in the nucleus. Such activation may cause the secretion of certain signaling molecule(s), which inhibit the PKC pathway. Our study provides a novel pathway of E2 action that could be a therapeutic target to activate matrix mineralization under various diseases, including osteoporosis.

Funder

Grants-in-Aid for Scientific Research

Publisher

MDPI AG

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