Effects of bone morphogenetic protein (BMP) on adrenocorticotropin production by pituitary corticotrope cells: Involvement of up-regulation of bmp receptor signaling by somatostatin analogs

Naoko Tsukamoto, Fumio Otsuka, Tomoko Miyoshi, Ryutaro Yamanaka, Kenichi Inagaki, Misuzu Yamashita, Hiroyuki Otani, Masaya Takeda, Jiro Suzuki, Toshio Ogura, Yasumasa Iwasaki, Hirofumi Makino

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Abstract

The mechanism by which somatostatin analogs suppress ACTH production by corticotropinomas has yet to be fully elucidated. We here studied the effects of somatostatin analogs on ACTH secretion using mouse corticotrope AtT20 cells focusing on the biological activity of bone morphogenetic proteins (BMPs). BMP ligands, receptors and Smads, and somatostatin receptors (SSTRs)-2, -3, and -5 were expressed in AtT20 cells. BMP-2, -4, -6, and -7 decreased basal ACTH production with BMP-4 effects being the most prominent. BMP-4 also inhibited CRH-inducedACTH production and proopiomelanocortin (POMC) transcription. However, the decrease in CRH-induced cAMP accumulation caused by BMP-4 was not sufficient to completely account for BMP-4 actions, indicating that ACTH suppression by BMPs was not directly linked to cAMP inhibition. CRH-activated ERK1/ERK2, p38-MAPK, stress-activated protein kinase/c-Jun NH2-terminal kinase, protein kinase C, and Akt pathways and CRH-induced ACTH synthesis was significantly decreased in the presence of U0126 or SB203580. Because BMPs attenuated CRH-induced ERK and p38 phosphorylation, it was suggested that BMP-4 suppresses ACTH production by inhibiting CRH-induced ERK and p38 phosphorylation. Somatostatin analogs octreotide and pasireotide (SOM230) significantly suppressed CRH-induced ACTH and cAMP production in AtT20 cells and reduced ERK and p38 phosphorylation. Notably, CRH-induced ACTH production was enhanced in the presence of noggin, a BMP-binding protein. The inhibitory effects of octreotide and SOM230 on CRH-induced ACTHproductionwerealso attenuated by noggin, implying that the endogenous BMP system plays a key role in inhibiting CRH-induced ACTH production by AtT20 cells. The findings that OCT and SOM230 up-regulated BMP-Smad1/Smad5/Smad8 signaling and ALK-3 and BMPRII and downregulated inhibitory Smad6/7 establish that the activation of endogenous BMP system is functionally involved in the mechanism by which somatostatin analogs suppress CRH-induced ACTH production.

Original languageEnglish
Pages (from-to)1129-1141
Number of pages13
JournalEndocrinology
Volume151
Issue number3
DOIs
Publication statusPublished - Mar 2010

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Bone Morphogenetic Proteins
Somatostatin
Adrenocorticotropic Hormone
Bone Morphogenetic Protein 4
Up-Regulation
Octreotide
Phosphorylation
Bone Morphogenetic Protein Receptors
Bone Morphogenetic Protein 2
Pro-Opiomelanocortin
JNK Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
Heat-Shock Proteins
Protein Binding
Protein Kinases
Protein Kinase C
Carrier Proteins
Down-Regulation
Ligands

ASJC Scopus subject areas

  • Endocrinology

Cite this

Effects of bone morphogenetic protein (BMP) on adrenocorticotropin production by pituitary corticotrope cells : Involvement of up-regulation of bmp receptor signaling by somatostatin analogs. / Tsukamoto, Naoko; Otsuka, Fumio; Miyoshi, Tomoko; Yamanaka, Ryutaro; Inagaki, Kenichi; Yamashita, Misuzu; Otani, Hiroyuki; Takeda, Masaya; Suzuki, Jiro; Ogura, Toshio; Iwasaki, Yasumasa; Makino, Hirofumi.

In: Endocrinology, Vol. 151, No. 3, 03.2010, p. 1129-1141.

Research output: Contribution to journalArticle

Tsukamoto, Naoko ; Otsuka, Fumio ; Miyoshi, Tomoko ; Yamanaka, Ryutaro ; Inagaki, Kenichi ; Yamashita, Misuzu ; Otani, Hiroyuki ; Takeda, Masaya ; Suzuki, Jiro ; Ogura, Toshio ; Iwasaki, Yasumasa ; Makino, Hirofumi. / Effects of bone morphogenetic protein (BMP) on adrenocorticotropin production by pituitary corticotrope cells : Involvement of up-regulation of bmp receptor signaling by somatostatin analogs. In: Endocrinology. 2010 ; Vol. 151, No. 3. pp. 1129-1141.
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abstract = "The mechanism by which somatostatin analogs suppress ACTH production by corticotropinomas has yet to be fully elucidated. We here studied the effects of somatostatin analogs on ACTH secretion using mouse corticotrope AtT20 cells focusing on the biological activity of bone morphogenetic proteins (BMPs). BMP ligands, receptors and Smads, and somatostatin receptors (SSTRs)-2, -3, and -5 were expressed in AtT20 cells. BMP-2, -4, -6, and -7 decreased basal ACTH production with BMP-4 effects being the most prominent. BMP-4 also inhibited CRH-inducedACTH production and proopiomelanocortin (POMC) transcription. However, the decrease in CRH-induced cAMP accumulation caused by BMP-4 was not sufficient to completely account for BMP-4 actions, indicating that ACTH suppression by BMPs was not directly linked to cAMP inhibition. CRH-activated ERK1/ERK2, p38-MAPK, stress-activated protein kinase/c-Jun NH2-terminal kinase, protein kinase C, and Akt pathways and CRH-induced ACTH synthesis was significantly decreased in the presence of U0126 or SB203580. Because BMPs attenuated CRH-induced ERK and p38 phosphorylation, it was suggested that BMP-4 suppresses ACTH production by inhibiting CRH-induced ERK and p38 phosphorylation. Somatostatin analogs octreotide and pasireotide (SOM230) significantly suppressed CRH-induced ACTH and cAMP production in AtT20 cells and reduced ERK and p38 phosphorylation. Notably, CRH-induced ACTH production was enhanced in the presence of noggin, a BMP-binding protein. The inhibitory effects of octreotide and SOM230 on CRH-induced ACTHproductionwerealso attenuated by noggin, implying that the endogenous BMP system plays a key role in inhibiting CRH-induced ACTH production by AtT20 cells. The findings that OCT and SOM230 up-regulated BMP-Smad1/Smad5/Smad8 signaling and ALK-3 and BMPRII and downregulated inhibitory Smad6/7 establish that the activation of endogenous BMP system is functionally involved in the mechanism by which somatostatin analogs suppress CRH-induced ACTH production.",
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AU - Otsuka, Fumio

AU - Miyoshi, Tomoko

AU - Yamanaka, Ryutaro

AU - Inagaki, Kenichi

AU - Yamashita, Misuzu

AU - Otani, Hiroyuki

AU - Takeda, Masaya

AU - Suzuki, Jiro

AU - Ogura, Toshio

AU - Iwasaki, Yasumasa

AU - Makino, Hirofumi

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