Effects of Bone Morphogenetic Protein (BMP) on Adrenocorticotropin Production by Pituitary Corticotrope Cells: Involvement of Up-Regulation of BMP Receptor Signaling by Somatostatin Analogs

Jan 9, 2010Endocrinology

Bone Morphogenetic Protein's Effects on Stress Hormone Release by Pituitary Cells and Its Increase by Somatostatin-Like Drugs

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

BMP-4 significantly decreased basal ACTH production in mouse corticotrope AtT20 cells.

BMP-4 had the most pronounced effect among BMPs, inhibiting both basal and CRH-induced ACTH production.
The reduction in ACTH production by BMP-4 was not fully explained by its effects on cAMP levels.
BMP-4 was shown to suppress CRH-induced phosphorylation of ERK and p38 pathways, which are involved in ACTH synthesis.
Somatostatin analogs octreotide and pasireotide reduced both CRH-induced ACTH and cAMP production while also decreasing ERK and p38 phosphorylation.
The presence of noggin, a BMP-binding protein, enhanced CRH-induced ACTH production and diminished the inhibitory effects of somatostatin analogs.

AI simplified

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.

Full Text

Full text is available at the source.

View full text (PDF) ↗View full text ↗

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

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief