A novel role for bone morphogenetic proteins in the synthesis of follicle-stimulating hormone.
A novel role for bone morphogenetic proteins in the synthesis of follicle-stimulating hormone.
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DOI：
10.1210/endo.142.6.8159
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发表时间：
2001-06
期刊：
影响因子：
4.8
通讯作者：
Huey-Jing Huang;Joyce C. Wu;P. Su;Oksana V. Zhirnov;William L. Miller
中科院分区：
文献类型：
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作者：
Huey-Jing Huang;Joyce C. Wu;P. Su;Oksana V. Zhirnov;William L. Miller
FSH在垂体促性腺激素中以α/β异源二聚体形式产生，β亚基的合成是整个FSH产生的限速步骤。FSH β的合成可由活化素和β-胡萝卜素调节，两者都是转化生长因子β超家族的成员。骨形态发生蛋白（BMP）也属于转化生长因子β家族，是多功能生长因子，参与组织发育和形态发生的许多方面，包括卵巢中FSH作用的调节。在这里，我们报告了一个新的功能，BMP-7和BMP-6在调节FSH的合成垂体。使用来自转基因小鼠的原代垂体细胞培养物，发现BMP-7或BMP-6刺激6倍的oFSH β Luc表达，所述转基因小鼠携带与荧光素酶报告基因（oFSH β Luc）连接的绵羊FSH β启动子。BMP-7或BMP-6处理诱导转化的促性腺细胞系LbetaT 2中oFSH betaLuc的瞬时表达4倍。更重要的是，BMP-7和BMP-6分别使LbetaT 2细胞的内源性FSH分泌增加了10倍和14倍，这首次证明了促性腺激素中存在功能性BMP信号系统。与BMP-6交叉反应但不与激活素A交叉反应的两种针对BMP-7的生物中和抗体分别使转基因小鼠垂体培养物的基础FSH β Luc表达和FSH分泌降低83-88%和47- 48%，表明BMP-7或BMP-6在FSH合成中的自分泌或旁分泌作用。激活素A或激活素B的生物中和抗体均未显著降低基础oFSH β Luc表达或小鼠FSH分泌。在大鼠和绵羊垂体培养物中也观察到抗BMP 7对FSH合成的剂量依赖性抑制。这些结果结合在小鼠垂体和LbetaT 2细胞中检测到BMP-7和BMP-6的信使RNA的事实表明，BMP-7和/或BMP-6可以作为FSH刺激剂起作用，并且可能是维持体内基础FSH表达的重要生理因子。
FSH is produced in pituitary gonadotropes as an alpha/beta heterodimer, and synthesis of the beta-subunit is the rate-limiting step in overall FSH production. Synthesis of FSHbeta can be regulated by activin and inhibin, both of which are members of the transforming growth factor-beta superfamily. Bone morphogenetic proteins (BMPs) also belong to the transforming growth factor-beta family and are multifunctional growth factors involved in many aspects of tissue development and morphogenesis, including regulation of FSH action in the ovary. Here we report a novel function for BMP-7 and BMP-6 in regulating FSH synthesis in the pituitary. Using primary pituitary cell cultures derived from transgenic mice that carry the ovine FSHbeta promoter linked to a luciferase reporter gene (oFSHbetaLuc), BMP-7 or BMP-6 was found to stimulate oFSHbetaLuc expression by 6-fold. Transient expression of the oFSHbetaLuc in a transformed gonadotrope cell line, LbetaT2, was induced 4-fold by BMP-7 or BMP-6 treatment. More importantly, BMP-7 and BMP-6 increased endogenous FSH secretion by 10- and 14-fold, respectively, from LbetaT2 cells, demonstrating for the first time that a functional signaling BMP system is present in gonadotropes. Two bioneutralizing antibodies to BMP-7, which cross-react with BMP-6, but not with activin A, decreased basal oFSHbetaLuc expression and FSH secretion from transgenic mouse pituitary cultures by 83-88% and 47-48%, respectively, suggesting an autocrine or paracrine role for BMP-7 or BMP-6 in FSH synthesis. Neither bioneutralizing antibody to activin A or activin B decreased basal oFSHbetaLuc expression or mouse FSH secretion significantly. Dose-dependent inhibition of FSH synthesis by anti-BMP7 was also observed in rat and sheep pituitary cultures. These results combined with the fact that the messenger RNAs for BMP-7 and BMP-6 were detected in mouse pituitaries and LbetaT2 cells indicate that BMP-7 and/or BMP-6 can function as FSH stimulators and may be significant physiological factors maintaining basal FSH expression in vivo.