Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β family of proteins that have been implicated in the paracrine regulation of granulosa cell (GC) function, but whether responses to BMPs change with follicular size or interact with connective tissue growth factor (CTGF) or BMP antagonists (e.g., gremlin [GREM]) to directly affect GC function of cattle is unknown. Therefore, to determine the effects of BMP4 on proliferation and steroidogenesis of GCs and its interaction with GREM or CTGF, experiments were conducted using bovine GC cultures. In vitro, BMP4 (30 ng/mL) inhibited (P < 0.05) follicle-stimulating hormone (FSH) plus insulin-like growth factor 1 (IGF1)-induced progesterone and estradiol production by large- and small-follicle GCs, but the inhibitory effect of BMP4 on estradiol production was much more pronounced in large-follicle GCs. In small-follicle GCs, BMP4 had no effect (P > 0.10) on IGF1-induced proliferation, but GREM inhibited (P < 0.05) cell proliferation and estradiol and progesterone production in IGF1 plus FSH-treated GCs. In large-follicle GCs, BMP4 (10 to 30 ng/mL) increased (P < 0.05) GC numbers and GREM (100 ng/mL) blocked this effect. In large-follicle GCs, CTGF inhibited (P < 0.05) FSH plus IGF1-induced progesterone and estradiol production, and CTGF blocked the stimulatory effect of BMP4 on GC proliferation. These results indicate that BMP4, GREM, and CTGF inhibit GC aromatase activity and progesterone production. Also, the stimulatory effect of BMP4 on GC proliferation and the inhibitory effects of BMP4 on GC steroidogenesis are more pronounced in large vs. small follicles.

中文翻译：

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骨形态发生蛋白 4、gremlin 和结缔组织生长因子对牛颗粒细胞产生雌二醇和黄体酮的影响

骨形态发生蛋白 (BMP) 是转化生长因子-β 蛋白家族的成员，这些蛋白与颗粒细胞 (GC) 功能的旁分泌调节有关，但对 BMP 的反应是否随滤泡大小而变化或与结缔组织生长因子相互作用(CTGF) 或 BMP 拮抗剂 (例如，gremlin [GREM]) 是否直接影响牛的 GC 功能是未知的。因此，为了确定 BMP4 对 GC 增殖和类固醇生成的影响及其与 GREM 或 CTGF 的相互作用，使用牛 GC 培养物进行了实验。在体外，BMP4 (30 ng/mL) 抑制 (P < 0.05) 促卵泡激素 (FSH) 和胰岛素样生长因子 1 (IGF1) 诱导的大卵泡和小卵泡 GC 产生的孕酮和雌二醇，但 BMP4 对雌二醇产生的抑制作用在大卵泡 GC 中更为明显。在小卵泡 GC 中，BMP4 对 IGF1 诱导的增殖没有影响（P > 0.10），但 GREM 抑制（P < 0.05）IGF1 加 FSH 处理的 GC 中的细胞增殖以及雌二醇和孕酮的产生。在大滤泡 GC 中，BMP4（10 至 30 ng/mL）增加（P < 0.05）GC 数量，而 GREM（100 ng/mL）阻止了这种作用。在大卵泡 GCs 中，CTGF 抑制 (P < 0.05) FSH 加 IGF1 诱导的孕酮和雌二醇产生，并且 CTGF 阻断 BMP4 对 GC 增殖的刺激作用。这些结果表明 BMP4、GREM 和 CTGF 抑制 GC 芳香酶活性和孕酮产生。还，