Otsuka F, Moore R K, Shimasaki S
Department of Reproductive Medicine, University of California San Diego, School of Medicine, La Jolla, California 92093-0633, USA.
J Biol Chem. 2001 Aug 31;276(35):32889-95. doi: 10.1074/jbc.M103212200. Epub 2001 Jul 10.
The process of ovarian folliculogenesis is composed of proliferation and differentiation of the constitutive cells in developing follicles. Growth factors emitted by oocytes integrate and promote this process. Growth differentiation factor-9 (GDF-9), bone morphogenetic protein (BMP)-15, and BMP-6 are oocyte-derived members of the transforming growth factor-beta superfamily. In contrast to the recent studies on GDF-9 and BMP-15, nothing is known about the biological function of BMP-6 in the ovary. Here we show that, unlike BMP-15 and GDF-9, BMP-6 lacks mitogenic activity on rat granulosa cells (GCs) and produces a marked decrease in follicle-stimulating hormone (FSH)-induced progesterone (P(4)) but not estradiol (E(2)) production, demonstrating not only the first identification of GCs as BMP-6 targets in the ovary but also its selective modulation of FSH action in steroidogenesis. This BMP-6 activity resembles BMP-15 but differs from GDF-9 activities. BMP-6 also exhibited similar action to BMP-15 by attenuating the steady state mRNA levels of FSH-induced steroidogenic acute regulatory protein (StAR) and P450 side-chain cleavage enzyme (P450scc), without affecting P450 aromatase mRNA level, supporting its differential function on FSH-regulated P(4) and E(2) production. However, unlike BMP-15, BMP-6 inhibited forskolin- but not 8-bromo-cAMP-induced P(4) production and StAR and P450scc mRNA expression. BMP-6 also decreased FSH- and forskolin-stimulated cAMP production, suggesting that the underlying mechanism by which BMP-6 inhibits FSH action most likely involves the down-regulation of adenylate cyclase activity. This is clearly distinct from the mechanism of BMP-15 action, which causes the suppression of basal FSH receptor (FSH-R) expression, without affecting adenylate cyclase activity. As assumed, BMP-6 did not alter basal FSH-R mRNA levels, whereas it inhibited FSH- and forskolin- but not 8-bromo-cAMP-induced FSH-R mRNA accumulation. These studies provide the first insight into the biological function of BMP-6 in the ovary and demonstrate its unique mechanism of regulating FSH action.
卵巢卵泡发生过程由发育中卵泡内组成细胞的增殖和分化构成。卵母细胞分泌的生长因子整合并促进这一过程。生长分化因子9（GDF-9）、骨形态发生蛋白（BMP）-15和BMP-6是转化生长因子-β超家族中来源于卵母细胞的成员。与最近关于GDF-9和BMP-15的研究不同，关于BMP-6在卵巢中的生物学功能尚无定论。在此我们表明，与BMP-15和GDF-9不同，BMP-6对大鼠颗粒细胞（GCs）缺乏促有丝分裂活性，且能显著降低促卵泡激素（FSH）诱导的孕酮（P(4)）生成，但不影响雌二醇（E(2)）生成，这不仅首次证实GCs是卵巢中BMP-6的作用靶点，还表明其在类固醇生成中对FSH作用具有选择性调节作用。这种BMP-6的活性类似于BMP-15，但不同于GDF-9的活性。BMP-6还通过降低FSH诱导的类固醇生成急性调节蛋白（StAR）和P450侧链裂解酶（P450scc）的稳态mRNA水平，表现出与BMP-15相似的作用，而不影响P450芳香化酶mRNA水平，支持其在FSH调节P(4)和E(2)生成方面的差异功能。然而，与BMP-15不同，BMP-6抑制福斯可林诱导的而非8-溴-cAMP诱导的P(4)生成以及StAR和P450scc mRNA表达。BMP-亦降低FSH和福斯可林刺激的cAMP生成，提示BMP-6抑制FSH作用的潜在机制很可能涉及腺苷酸环化酶活性的下调。这明显不同于BMP-15的作用机制，后者导致基础促卵泡激素受体（FSH-R）表达受抑制，而不影响腺苷酸环化酶活性。正如所推测的，BMP-6不改变基础FSH-R mRNA水平，而抑制FSH和福斯可林诱导的而非8-溴-cAMP诱导的FSH-R mRNA积累。这些研究首次深入了解了BMP-6在卵巢中的生物学功能，并证明了其调节FSH作用的独特机制。
