Involvement of bone morphogenetic protein-4 in GH regulation by octreotide and bromocriptine in rat pituitary GH3 cells
Involvement of bone morphogenetic protein-4 in GH regulation by octreotide and bromocriptine in rat pituitary GH3 cells
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DOI：
10.1677/joe-07-0549
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发表时间：
2008-04-01
影响因子：
4
通讯作者：
Makino, Hirofumi
中科院分区：
文献类型：
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作者：
Miyoshi, Tomoko;Otsuka, Fumio;Makino, Hirofumi
在这里，我们研究了垂体骨形态发生蛋白（BMP）系统在调节生长抑素类似物奥曲肽（OCT）和多巴胺激动剂溴隐亭（BRC）在大鼠垂体促泌乳素肿瘤GH3细胞中调节GH产生中的作用。 GH3细胞表达BMP配体，包括BMP-4和BMP-6-1 BMP 1型和2型受体（1型受体、激活素受体样激酶（ALK）-6除外）；和 Smad 信号分子。 Forskolin 根据 cAMP 合成刺激 GH 产生。 BRC（而非 OCT）抑制毛喉素诱导的 GH3 细胞的 cAMP 合成。 OCT 和 BRC 单独治疗可减少毛喉素诱导的 GH 分泌。低浓度（0-1μM）OCT与BRC（1-100μM）组合对减少毛喉素诱导的GH和cAMP产生表现出累加效应。然而，高浓度（10μM）的OCT与BRC组合未能抑制GH和cAMP的产生。 BMP-4 特异性增强 GH3 细胞中毛喉素诱导的 GH 分泌和 cAMP 产生。 BRC（而非 OCT）抑制 BMP4 诱导的 Smad1,5,8 磷酸化和 Id-1 转录激活，并降低 ALK-3 表达。值得注意的是，在高浓度 OCT 存在的情况下，抑制 BMP-4-Smad1,5,8 信号传导的 BRC 效应显着受损。在 BMP-4 存在的情况下，高浓度的 OCT 也减弱了 BRC 抑制毛喉素诱导的 GH 和 cAMP 产生的作用。总的来说，高浓度的 OCT 通过减少 GH3 细胞中 cAMP 的产生并抑制 BMP-4 信号传导来干扰 BRC 效应。这些发现可以解释 GH 减少对 OCT 和 BRC 联合治疗产生 GH 的垂体腺瘤的抵抗机制。
Here we investigated roles of the pituitary bone morphogenetic protein (BMP) system in modulating GH production regulated by a somatostatin analog, octreotide (OCT) and a dopamine agonist, bromocriptine (BRC) in rat pituitary somatolactotrope tumor GH3 cells. The GH3 cells were found to express BMP ligands, including BMP-4 and BMP-6-1 BMP type-1 and type-2 receptors (except the type-1 receptor, activin receptor-like kinase (ALK)-6); and Smad signaling molecules. Forskolin stimulated GH production in accordance with cAMP synthesis. BRC, but not OCT, suppressed forskolin-induced cAMP synthesis by GH3 cells. Individual treatment with OCT and BRC reduced forskolin-induced GH secretion. A low concentration (0-1 mu M) of OCT in combination with BRC (1-100 mu M) exhibited additive effects on reducing GH and cAMP production induced by forskolin. However, a high concentration (10 mu M) of OCT in combination with BRC failed to suppress GH and cAMP production. BMP-4 specifically enhanced GH secretion and cAMP production induced by forskolin in GH3 cells. BRC, but not OCT, inhibited BMP4-induced activation of Smad1,5,8 phosphorylation and Id-1 transcription and decreased ALK-3 expression. Of note, in the presence of a high concentration of OCT, the BRC effects suppressing BMP-4-Smad1,5,8 signaling were significantly impaired. In the presence of BMP-4, a high concentration of OCT also attenuated the BRC effects suppressing forskolin-induced GH and cAMP production. Collectively, a high concentration of OCT interferes with BRC effects by reducing cAMP production and suppressing BMP-4 signaling in GH3 cells. These findings may explain the mechanism of resistance of GH reduction to a combination therapy with OCT and BRC for GH-producing pituitary adenomas.