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.
Endocrinology. 2010 Mar;151(3):1129-41. doi: 10.1210/en.2009-1102. Epub 2010 Jan 7.
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.
生长抑素类似物抑制促肾上腺皮质激素细胞瘤 ACTH 产生的机制尚未完全阐明。我们在这里使用鼠 corticotrope AtT20 细胞研究了生长抑素类似物对 ACTH 分泌的影响，重点研究了骨形态发生蛋白 (BMPs) 的生物学活性。AtT20 细胞中表达 BMP 配体、受体和 Smads 以及生长抑素受体 (SSTR) -2、-3 和-5。BMP-2、-4、-6 和-7 降低了基础 ACTH 的产生，其中 BMP-4 的作用最为显著。BMP-4 还抑制了 CRH 诱导的 ACTH 产生和 proopiomelanocortin (POMC) 转录。然而，BMP-4 引起的 cAMP 积累减少不足以完全解释 BMP-4 的作用，表明 BMP 对 ACTH 的抑制作用与 cAMP 抑制无关。CRH 激活的 ERK1/ERK2、p38-MAPK、应激激活蛋白激酶/c-Jun NH2-末端激酶、蛋白激酶 C 和 Akt 途径以及 CRH 诱导的 ACTH 合成在 U0126 或 SB203580 的存在下显著减少。由于 BMPs 减弱了 CRH 诱导的 ERK 和 p38 磷酸化，因此推测 BMP-4 通过抑制 CRH 诱导的 ERK 和 p38 磷酸化来抑制 ACTH 的产生。生长抑素类似物奥曲肽和帕瑞肽 (SOM230) 显著抑制了 AtT20 细胞中 CRH 诱导的 ACTH 和 cAMP 的产生，并降低了 ERK 和 p38 的磷酸化。值得注意的是，noggin，一种 BMP 结合蛋白，增强了 CRH 诱导的 ACTH 产生。奥曲肽和 SOM230 对 CRH 诱导的 ACTH 产生的抑制作用也被 noggin 减弱，这表明内源性 BMP 系统在抑制 AtT20 细胞中 CRH 诱导的 ACTH 产生中起着关键作用。OCT 和 SOM230 上调 BMP-Smad1/Smad5/Smad8 信号和 ALK-3 和 BMPRII 以及下调抑制性 Smad6/7 的发现表明，内源性 BMP 系统的激活在生长抑素类似物抑制 CRH 诱导的 ACTH 产生的机制中具有功能相关性。
