Functional relationship between fibroblast growth factor-8 and bone morphogenetic proteins in regulating steroidogenesis by rat granulosa cells
Functional relationship between fibroblast growth factor-8 and bone morphogenetic proteins in regulating steroidogenesis by rat granulosa cells
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DOI：
10.1016/j.mce.2010.04.012
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发表时间：
2010-08-30
影响因子：
4.1
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
骨形态发生蛋白（BMPs）被认为是调节卵巢生理的关键分子，不同的BMPs在FSH诱导的雌二醇产生中具有不同的作用。为了确定卵母细胞因子的作用，调节类固醇激素的骨形成蛋白控制，我们在这里研究了FGF-8在大鼠颗粒/卵母细胞共培养的影响。FGF-8有效地抑制FSH诱导的雌二醇产生，但不影响cAMP诱导的大鼠颗粒细胞产生的雌二醇。FGF-8对FSH和forskolin诱导的孕酮和cAMP的产生无影响。FGF-8对FSH诱导的雌二醇产生的抑制作用不被BMP-2、-4、-6或-7改变。在FGF-8的存在下，BMP通过减少cAMP抑制FSH诱导的孕酮，表明FGF-8和BMP独立地调节FSH受体信号传导。值得注意的是，FGF-8诱导颗粒细胞中的ERK和SAPK/JNK磷酸化，其中ERK活化被FSH和卵母细胞进一步增强。ERK和SAPK/JNK的抑制降低FSH诱导的孕酮和cAMP水平，表明这些途径的激活增强FSH诱导的cAMP信号传导。此外，ERK抑制上调FSH诱导的雌二醇合成，表明ERK途径也参与抑制颗粒细胞芳香化酶活性。有趣的是，FGF-8增强BMP诱导的Smad 1/5/8和Id-1启动子活性，同时降低Smad 6/7的表达。由于SAPK/JNK抑制剂抑制FGF-8上调Id-1转录的作用，因此SAPK/JNK似乎参与FGF-8增强BMP-Smad信号传导的机制。此外，在卵母细胞的存在下，内源性FGF受体信号的抑制抑制FSH和毛喉素诱导的孕酮和cAMP，表明内源性FGF系统参与通过ERK和SAPK/JNK激活FSH诱导的cAMP-PKA信号。因此，卵母细胞因子FGF-8不仅通过激活ERK抑制FSH诱导的雌二醇产生，而且还增强颗粒细胞中的BMP-Smad信号传导。FGF-8和BMPs之间的这种相互作用可能在通过卵母细胞-颗粒细胞通讯调节类固醇生成中起关键作用。(C)2010爱思唯尔爱尔兰有限公司版权所有。
Bone morphogenetic proteins (BMPs) have been recognized as crucial molecules in regulating ovarian physiology, with different BMPs having differential actions in FSH-induced estradiol production. To identify the roles of oocyte factors that modulate steroidogenesis controlled by BMPs, we here investigated the effects of FGF-8 in rat granulosa/oocyte co-cultures. FGF-8 potently suppressed FSH-induced estradiol production, but did not affect cAMP-induced estradiol produced by rat granulosa cells. FGF-8 had no effects on progesterone and cAMP production induced by FSH and forskolin. The inhibitory effects of FGF-8 on FSH-induced estradiol production were not altered by BMP-2, -4, -6 or -7. In the presence of FGF-8, BMPs suppressed FSH-induced progesterone by reducing cAMP, suggesting that FGF-8 and BMP independently regulate FSH receptor signaling. Notably, FGF-8-induced ERK and SAPK/JNK phosphorylation in granulosa cells, in which ERK activation was further enhanced by FSH and oocytes. Inhibition of ERK and SAPK/JNK reduced FSH-induced progesterone and cAMP levels, suggesting that the activation of these pathways enhances FSH-induced cAMP signaling. In addition, ERK inhibition upregulated FSH-induced estradiol synthesis, indicating that ERK pathway is also involved in suppressing aromatase activity in granulosa cells. Interestingly, FGF-8 enhanced BMP-induced Smad1/5/8 and Id-1-promoter activities with decreased expression of Smad6/7. Since the SAPK/JNK inhibitor inhibited FGF-8 effects in upregulating Id-1 transcription, SAPK/JNK appears to be involved in the mechanism by which FGF-8 enhances BMP-Smad signaling. Furthermore, in the presence of oocytes, the inhibition of endogenous FGF receptor signaling suppressed FSH- and forskolin-induced progesterone and cAMP, showing that endogenous FGF system is involved in activation of FSH-induced cAMP-PKA signaling via ERK and SAPK/JNK. Thus, the oocyte factor, FGF-8, not only suppresses FSH-induced estradiol production by activating ERK, but also enhances BMP-Smad signaling in granulosa cells. This interaction between FGF-8 and BMPs may play a key role in regulating steroidogenesis through oocyte-granulosa cell communication. (C) 2010 Elsevier Ireland Ltd. All rights reserved.