title: BMP-6 modulates somatostatin effects on luteinizing hormone production by gonadrotrope cells.
abstract: The effects of somatostatin analogs and roles of BMP-6 in the regulation of luteinizing hormone (LH) secretion were investigated using mouse gonadotrope LβT2 cells. LH mRNA expression and LH secretion induced by GnRH were suppressed by treatments with somatostatin analogs, including octreotide and pasireotide, in LβT2 cells. Of note, the inhibitory effects of somatostatin analogs on LH secretion were enhanced by the action of BMP-6. BMP-6 increased the expression levels of somatostatin receptor (SSTR)5, suggesting that BMP-6 upregulates SSTR activity that leads to reduction of GnRH-induced LH secretion. In addition, GnRH-induced phosphorylation of MAPKs including ERK, but not P38 or SAPK, was suppressed by pasireotide in the presence of BMP-6. Given that each inhibitor of ERK, JNK or P38 signaling suppressed GnRH-induced LH transcription, MAPKs are individually involved in the induction of LH production by LβT2 cells. Somatostatin analogs also impaired BMP-6-induced Smad1/5/8 phosphorylation by suppressing BMPRs and augmenting Smad6/7 expression. Collectively, the results indicate that somatostatin analogs have dual effects on the modulation of GnRH-induced MAPK signaling and BMP activity. The pituitary BMP system may play a regulatory role in GnRH-induced LH secretion by tuning the responsiveness to somatostatin analogs in gonadotrope cells.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Kishio
authors.initials: K
authors.lastname: Toma
authors.affiliation: Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. Electronic address: fumiotsu@md.okayama-u.ac.jp.
authors.forename: Fumio
authors.initials: F
authors.lastname: Otsuka
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Oguni
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Terasaka
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Motoshi
authors.initials: M
authors.lastname: Komatsubara
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Tsukamoto-Yamauchi
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Inagaki
authors.affiliation: Okayama University Hospital, Okayama, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000502:physiology*; D002460:Cell Line; D052681:Gonadotrophs / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006801:Humans; D007986:Luteinizing Hormone / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D013004:Somatostatin / Q000502:physiology*
chemical_list: C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D007987:Gonadotropin-Releasing Hormone; D013004:Somatostatin; D007986:Luteinizing Hormone
keywords: Bone morphogenetic protein; Gonadotrope; Gonadotropin-releasing hormone; Luteinizing hormone; Somatostatin