title: Effects of bone morphogenetic protein (BMP) on adrenocorticotropin production by pituitary corticotrope cells: involvement of up-regulation of BMP receptor signaling by somatostatin analogs.
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-induced ACTH 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 NH(2)-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 ACTH production were also 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 down-regulated 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.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kitaku, Okayama 700-8558, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Tsukamoto
authors.forename: Fumio
authors.initials: F
authors.lastname: Otsuka
authors.forename: Tomoko
authors.initials: T
authors.lastname: Miyoshi
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Yamanaka
authors.forename: Kenichi
authors.initials: K
authors.lastname: Inagaki
authors.forename: Misuzu
authors.initials: M
authors.lastname: Yamashita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Otani
authors.forename: Masaya
authors.initials: M
authors.lastname: Takeda
authors.forename: Jiro
authors.initials: J
authors.lastname: Suzuki
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogura
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D002460:Cell Line; D052680:Corticotrophs / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D051785:Smad Proteins / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D051785:Smad Proteins; D013004:Somatostatin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases