Nicol L, Faure M-O, McNeilly J R, Fontaine J, Taragnat C, McNeilly A S
MRC Human Reproductive Sciences Unit, The Queen's Medical Research Institute, Centre for Reproductive Biology, 47 Little France Crescent, Edinburgh, EH16 4TJ UK.
J Endocrinol. 2008 Mar;196(3):497-507. doi: 10.1677/JOE-07-0542.
We have shown previously that, in sheep primary pituitary cells, bone morphogenetic proteins (BMP)-4 inhibits FSHbeta mRNA expression and FSH release. In contrast, in mouse LbetaT2 gonadotrophs, others have shown a stimulatory effect of BMPs on basal or activin-stimulated FSHbeta promoter-driven transcription. As a species comparison with our previous results, we used LbetaT2 cells to investigate the effects of BMP-4 on gonadotrophin mRNA and secretion modulated by activin and GnRH. BMP-4 alone had no effect on FSH production, but enhanced the activin+GnRH-induced stimulation of FSHbeta mRNA and FSH secretion, without any effect on follistatin mRNA. BMP-4 reduced LHbeta mRNA up-regulation in response to GnRH (+/-activin) and decreased GnRH receptor expression, which would favour FSH, rather than LH, synthesis and secretion. In contrast to sheep pituitary gonadotrophs, which express only BMP receptor types IA (BMPRIA) and II (BMPRII), LbetaT2 cells also express BMPRIB. Smad1/5 phosphorylation induced by BMP-4, indicating activation of BMP signalling, was the same whether BMP-4 was used alone or combined with activin+/-GnRH. We hypothesized that activin and/or GnRH pathways may be modulated by BMP-4, but neither the activin-stimulated phosphorylation of Smad2/3 nor the GnRH-induced ERK1/2 or cAMP response element-binding phosphorylation were modified. However, the GnRH-induced activation of p38 MAPK was decreased by BMP-4. This was associated with increased FSHbeta mRNA levels and FSH secretion, but decreased LHbeta mRNA levels. These results confirm 1. BMPs as important modulators of activin and/or GnRH-stimulated gonadotrophin synthesis and release and 2. important species differences in these effects, which could relate to differences in BMP receptor expression in gonadotrophs.
我们之前已经表明，在绵羊原代垂体细胞中，骨形态发生蛋白（BMP）-4可抑制促卵泡激素β（FSHβ）mRNA表达和FSH释放。相比之下，在小鼠LβT2促性腺激素细胞中，其他人已表明BMP对基础或激活素刺激的FSHβ启动子驱动的转录具有刺激作用。作为与我们之前结果的物种比较，我们使用LβT2细胞来研究BMP-4对由激活素和促性腺激素释放激素（GnRH）调节的促性腺激素mRNA和分泌的影响。单独的BMP-4对FSH产生没有影响，但增强了激活素+GnRH诱导的FSHβmRNA和FSH分泌的刺激作用，而对卵泡抑素mRNA没有任何影响。BMP-4减少了对GnRH（±激活素）的反应中促黄体生成素β（LHβ）mRNA的上调，并降低了GnRH受体表达，这有利于FSH而非LH的合成和分泌。与仅表达I型（BMPRIA）和II型（BMPRII）BMP受体的绵羊垂体促性腺激素细胞不同，LβT2细胞还表达BMPRIB。无论BMP-4单独使用还是与激活素+/-GnRH联合使用，BMP-4诱导的Smad1/5磷酸化（表明BMP信号激活）都是相同的。我们假设激活素和/或GnRH途径可能受到BMP-4的调节，但激活素刺激的Smad2/3磷酸化以及GnRH诱导的细胞外信号调节激酶1/2（ERK1/2）或环磷酸腺苷反应元件结合蛋白（CREB）磷酸化均未改变。然而，BMP-4降低了GnRH诱导的p38丝裂原活化蛋白激酶（p38 MAPK）的激活。这与FSHβmRNA水平升高和FSH分泌增加相关，但LHβmRNA水平降低。这些结果证实了1. BMP是激活素和/或GnRH刺激的促性腺激素合成和释放的重要调节因子，以及2. 这些作用中存在重要的物种差异，这可能与促性腺激素细胞中BMP受体表达的差异有关。
