Lee Katharine B, Khivansara Vishal, Santos Michelle M, Lamba Pankaj, Yuen Tony, Sealfon Stuart C, Bernard Daniel J
Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montréal, Québec, Canada H3G 1Y6.
J Mol Endocrinol. 2007 Feb;38(1-2):315-30. doi: 10.1677/jme.1.02196.
Transforming growth factor beta superfamily ligands regulate pituitary FSH production and secretion. The best-described examples are the activins and inhibins, which respectively stimulate and hinder Fshb subunit transcription in gonadotrope cells. More recently, members of the bone morphogenetic protein (BMP) sub-family were shown to regulate FSH production in a manner analogous to the activins. Here, we used the murine gonadotrope cell line, LbetaT2, to investigate mechanisms through which BMP2 regulates the Fshb gene. Although expressed at low levels in LbetaT2 cells, Bmp2 mRNA was readily detected in adult murine pituitary gland. Recombinant BMP2 stimulated Fshb promoter-reporter activity, although its effects were weaker than those of equimolar activin A or B. BMP4 stimulated transcription comparably with BMP2, but BMPs 6 and 7 were about tenfold less potent. Remarkably, BMP2 and activin A synergistically upregulated Fshb transcription and endogenous Fshb mRNA levels in LbetaT2 cells. Although functionally cooperative, the two ligands appeared to use distinct intracellular mechanisms to mediate their responses because neither ligand altered the timing or magnitude of the other's effects. Receptor overexpression analyses suggested that BMP2 may preferentially signal through complexes of the type II receptor, BMPR2, and the type I receptor, activin receptor like kinase (ALK2; Acvr1), to stimulate Fshb transcription. BMP2 rapidly activated the Smad1/5/8 intracellular signaling cascade and Smad8 overexpression potentiated BMP2's effects. In summary, BMPs regulate Fshb transcription in LbetaT2 cells and can amplify the already robust effects of the activins through a distinct signaling mechanism. Because BMP2 is expressed in the adult mouse pituitary, it may act as critical paracrine co-regulator of FSH synthesis by gonadotropes.
转化生长因子β超家族配体调节垂体促卵泡激素（FSH）的产生和分泌。最典型的例子是激活素和抑制素，它们分别刺激和阻碍促性腺激素细胞中Fshb亚基的转录。最近，骨形态发生蛋白（BMP）亚家族的成员被证明以类似于激活素的方式调节FSH的产生。在这里，我们使用小鼠促性腺激素细胞系LbetaT2来研究BMP2调节Fshb基因的机制。尽管Bmp2 mRNA在LbetaT2细胞中表达水平较低，但在成年小鼠垂体中很容易检测到。重组BMP2刺激Fshb启动子-报告基因活性，尽管其作用比等摩尔的激活素A或B弱。BMP4刺激转录的效果与BMP2相当，但BMP6和BMP7的效力约低10倍。值得注意的是，BMP2和激活素A协同上调LbetaT2细胞中Fshb的转录和内源性Fshb mRNA水平。尽管在功能上具有协同作用，但这两种配体似乎使用不同的细胞内机制来介导它们的反应，因为两种配体都不会改变对方作用的时间或强度。受体过表达分析表明，BMP2可能优先通过II型受体BMPR2和I型受体激活素受体样激酶（ALK2；Acvr1）的复合物发出信号，以刺激Fshb转录。BMP2迅速激活Smad1/5/8细胞内信号级联反应，Smad8的过表达增强了BMP2的作用。总之，BMP在LbetaT2细胞中调节Fshb转录，并可以通过独特的信号机制放大激活素已经很强的作用。由于BMP2在成年小鼠垂体中表达，它可能作为促性腺激素细胞合成FSH的关键旁分泌共调节因子。
