TY - JOUR
T1 - BMP-6 modulates somatostatin effects on luteinizing hormone production by gonadrotrope cells
AU - Toma, Kishio
AU - Otsuka, Fumio
AU - Oguni, Kohei
AU - Terasaka, Tomohiro
AU - Komatsubara, Motoshi
AU - Yamauchi, Naoko
AU - Inagaki, Kenichi
AU - Makino, Hirofumi
N1 - Funding Information:
FO receives speaker honoraria from Novo Nordisk. HM is a consultant for AbbVie, Astellas and Teijin, receives speaker honoraria from Astellas, Boehringer-ingelheim, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, MSD, Novartis, Pfizer, Takeda, and Tanabe Mitsubishi, and receives grant support from Astellas, Daiichi Sankyo, Dainippon Sumitomo, Kyowa Hakko Kirin, MSD, Novo Nordisk, Takeda, and Tanabe Mitsubishi.
Funding Information:
This work was supported in part by Grants-in-Aid for Scientific Research (No. 24591364 and 15K09434 ), Foundation for Growth Science and Astellas Foundation for Research on Metabolic Disorders , Japan Foundation for Applied Enzymology (Japan), and The Uehara Memorial Foundation .
Publisher Copyright:
© 2016 Elsevier Inc. All rights reserved.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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.
AB - 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.
KW - Bone morphogenetic protein
KW - Gonadotrope
KW - Gonadotropin-releasing hormone
KW - Luteinizing hormone
KW - Somatostatin
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U2 - 10.1016/j.peptides.2016.01.011
DO - 10.1016/j.peptides.2016.01.011
M3 - Article
C2 - 26779985
AN - SCOPUS:84955513599
SN - 0196-9781
VL - 76
SP - 96
EP - 101
JO - Peptides
JF - Peptides
ER -