Secreted frizzled-related protein-4 (SFRP4) belongs to a family of soluble ovarian-expressed proteins that participate in female reproduction, particularly in rodents. In humans, SFRP4 is highly expressed in cumulus cells (CCs). However, the mechanisms that stimulate SFRP4 in CCs have not been examined. We hypothesise that oocyte-secreted factors such as growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are involved in the regulation of SFRP4. Human CCs were collected from patients undergoing fertility treatments and treated with GDF9 or BMP15 or their combination in the presence of FSH or vehicle. FSH treatment significantly decreased SFRP4 mRNA levels when compared with nontreated cells. However, SFRP4 mRNA levels were increased significantly by GDF9 plus BMP15 in a concentration-dependent manner in the presence or absence of FSH. The combination of GDF9 plus BMP15 also increased SFRP4 protein levels and decreased the activity of the β-catenin/T cell factor-responsive promoter significantly. GDF9 plus BMP15 inhibited steroidogenic acute regulatory protein and LH/hCG receptor stimulation by FSH, while treatment with SFRP4 blocked the stimulatory effect of FSH on these genes. The evidence demonstrates that GDF9 and BMP15 act in coordination to stimulate SFRP4 expression and suggests that SFRP4 mediates the anti-luteinising effects of the oocyte in human CCs.

中文翻译：

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卵母细胞分泌因子强烈刺激人卵丘细胞中 sFRP4 的表达

分泌的卷曲相关蛋白 4 (SFRP4) 属于可溶性卵巢表达蛋白家族，参与雌性生殖，特别是在啮齿动物中。在人类中，SFRP4 在卵丘细胞 (CC) 中高度表达。然而，尚未检查在 CC 中刺激 SFRP4 的机制。我们假设卵母细胞分泌的因子如生长分化因子 9 (GDF9) 和骨形态发生蛋白 15 (BMP15) 参与了 SFRP4 的调节。从接受生育治疗的患者收集人类 CC，并在 FSH 或载体存在下用 GDF9 或 BMP15 或它们的组合治疗。与未处理的细胞相比，FSH 处理显着降低了 SFRP4 mRNA 水平。然而，在 FSH 存在或不存在的情况下，GDF9 加 BMP15 以浓度依赖性方式显着增加 SFRP4 mRNA 水平。GDF9 加 BMP15 的组合也显着增加了 SFRP4 蛋白水平并显着降低了 β-catenin/T 细胞因子反应启动子的活性。GDF9 加 BMP15 抑制 FSH 对类固醇生成急性调节蛋白和 LH/hCG 受体的刺激，而用 SFRP4 治疗则阻断了 FSH 对这些基因的刺激作用。证据表明 GDF9 和 BMP15 协同作用以刺激 SFRP4 表达，并表明 SFRP4 介导了人类 CCs 中卵母细胞的抗黄体生成作用。GDF9 加 BMP15 抑制 FSH 对类固醇生成急性调节蛋白和 LH/hCG 受体的刺激，而用 SFRP4 治疗则阻断了 FSH 对这些基因的刺激作用。证据表明 GDF9 和 BMP15 协同作用以刺激 SFRP4 表达，并表明 SFRP4 介导了人类 CCs 中卵母细胞的抗黄体生成作用。GDF9 加 BMP15 抑制 FSH 对类固醇生成急性调节蛋白和 LH/hCG 受体的刺激，而用 SFRP4 治疗则阻断了 FSH 对这些基因的刺激作用。证据表明 GDF9 和 BMP15 协同作用以刺激 SFRP4 表达，并表明 SFRP4 介导了人类 CCs 中卵母细胞的抗黄体生成作用。