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This Article Full Text Full Text (PDF) All Versions of this Article: JOE-09-0065v1 JOE-09-0065v2 203/1/87    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Otani, H. Articles by Makino, H. PubMed PubMed Citation Articles by Otani, H. Articles by Makino, H.

Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama City 700-8558, Japan
¹ Department of Reproductive Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA

(Correspondence should be addressed to F Otsuka; Email: fumiotsu{at}md.okayama-u.ac.jp)

Recent studies have shown that bone morphogenetic proteins (BMPs) are important regulators in the pituitary–gonadal endocrine axis. We here investigated the effects of BMPs on GNRH production controlled by estrogen using murine GT1-7 hypothalamic neuron cells. GT1-7 cells expressed estrogen receptor (ER; ESR1 as listed in MGI Database), ERβ (ESR2 as listed in MGI Database), BMP receptors, SMADs, and a binding protein follistatin. Treatment with BMP2 and BMP4 had no effect on Gnrh mRNA expression; however, BMP6 and BMP7 significantly increased Gnrh mRNA expression as well as GnRH production by GT1-7 cells. Notably, the reduction of Gnrh expression caused by estradiol (E₂) was restored by cotreatment with BMP2 and BMP4, whereas it was not affected by BMP6 or BMP7. E₂ activated extracellular signal-regulated kinase (ERK) 1/2 and stress-activated protein kinase/c-Jun NH₂-terminal kinase (SAPK/JNK) signaling but did not activate p38-mitogen-activated protein kinase (MAPK) signaling in GT1-7 cells. Inhibition of ERK1/ERK2 reversed the inhibitory effect of estrogen on Gnrh expression, whereas SAPK/JNK inhibition did not affect the E₂ actions. Expression levels of Er and Erβ were reduced by BMP2 and BMP4, but were increased by BMP6 and BMP7. Treatment with an ER antagonist inhibited the E₂ effects on Gnrh suppression including reduction of E₂-induced ERK phosphorylation, suggesting the involvement of genomic ER actions in Gnrh suppression. BMP2 and BMP4 also suppressed estrogen-induced phosphorylation of ERK1/ERK2 and SAPK/JNK signaling, suggesting that BMP2 and BMP4 downregulate estrogen effects by attenuating ER–MAPK signaling. Considering that BMP6 and BMP7 increased the expression of 1E-subunit of R-type calcium channel (Cacna1e), which is critical for GNRH secretion, it is possible that BMP6 and BMP7 directly stimulate GNRH release by GT1-7 cells. Collectively, a newly uncovered interaction of BMPs and ER may be involved in controlling hypothalamic GNRH production and secretion via an autocrine/paracrine mechanism.