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BMP2 increases the production of BDNF through the upregulation of proBDNF and furin expression in human granulosa‐lutein cells
The FASEB Journal ( IF 4.8 ) Pub Date : 2020-10-13 , DOI: 10.1096/fj.202000940r
Long Bai 1, 2 , Hsun‐Ming Chang 2 , Liang Zhang 3 , Yi‐Min Zhu 1 , Peter C. K. Leung 1, 2
Affiliation  

Locally produced in human granulosa cells of the developing follicle, bone morphogenetic protein 2 (BMP2) plays a crucial role in the regulation of ovarian folliculogenesis and luteal formation. Brain‐derived neurotrophic factor (BDNF) is an intraovarian neurotrophic factor that has been shown to promote oocyte maturation and subsequent fertilization competency. At present, little is known regarding the intracellular regulation, assembly and secretion of endogenous BDNF in human granulosa cells. The aim of this study was to explore the effect of BMP2 on the expression and production of BDNF in human granulosa cells and the molecular mechanisms underlying this effect. An immortalized human granulosa cell line (SVOG) and primary human granulosa‐lutein (hGL) cells were utilized as in vitro study models. Our results showed that BMP2 significantly increased the mRNA and secreted levels of BDNF. Additionally, BMP2 upregulated the expression of furin at the transcriptional and translational levels. Knockdown of endogenous furin partially attenuated the BMP2‐induced increase in BDNF production, indicating that furin is involved in the maturation process of BDNF. Using pharmacological (kinase receptor inhibitors) and siRNA‐mediated inhibition approaches, we demonstrated that BMP2‐induced upregulation of BDNF and furin expression is most likely mediated by the activin receptor‐like kinase (ALK)2/ALK3‐SMAD4 signaling pathway. Notably, analysis using clinical samples revealed that there was a positive correlation between follicular fluid concentrations of BMP2 and those of BDNF. These results indicate that BMP2 increases the production of mature BDNF by upregulating the precursor BDNF and promoting the proteolytic processing of mature BDNF. Finally, we also investigated the effects of BMP2 on ovarian steroidogenesis and the results showed that BMP2 treatment significantly increased the accumulated level of estradiol (by upregulating the expression of FSH receptor and cytochrome P450 aromatase), whereas it decreased the accumulated level of progesterone (by downregulating the expression of LH receptors and steroidogenic acute regulatory protein) in primary hGL cells. Our findings provide a novel paracrine mechanism underlying the regulation of an intraovarian growth factor in human granulosa cells.

中文翻译:

BMP2通过上调人颗粒叶黄素细胞中proBDNF和弗林蛋白酶的表达来增加BDNF的产生

在发育卵泡的人类颗粒细胞中局部产生的骨形态发生蛋白 2 (BMP2) 在调节卵巢卵泡发生和黄体形成中起着至关重要的作用。脑源性神经营养因子 (BDNF) 是一种卵巢内神经营养因子,已被证明可促进卵母细胞成熟和随后的受精能力。目前,关于人颗粒细胞中内源性BDNF的细胞内调节、组装和分泌知之甚少。本研究的目的是探讨 BMP2 对人颗粒细胞中 BDNF 表达和产生的影响以及这种影响背后的分子机制。使用永生化人颗粒细胞系 (SVOG) 和原代人颗粒叶黄素 (hGL) 细胞作为体外研究模型。我们的结果表明 BMP2 显着增加了 BDNF 的 mRNA 和分泌水平。此外,BMP2 在转录和翻译水平上调弗林蛋白酶的表达。内源性弗林蛋白酶的敲除部分减弱了 BMP2 诱导的 BDNF 产生的增加,表明弗林蛋白酶参与了 BDNF 的成熟过程。使用药理学(激酶受体抑制剂)和 siRNA 介导的抑制方法,我们证明 BMP2 诱导的 BDNF 和弗林蛋白酶表达上调最有可能由激活素受体样激酶 (ALK)2/ALK3-SMAD4 信号通路介导。值得注意的是,使用临床样本的分析表明,BMP2 的卵泡液浓度与 BDNF 的浓度呈正相关。这些结果表明 BMP2 通过上调前体 BDNF 和促进成熟 BDNF 的蛋白水解加工来增加成熟 BDNF 的产生。最后,我们还研究了 BMP2 对卵巢类固醇生成的影响,结果表明 BMP2 治疗显着增加了雌二醇的积累水平(通过上调 FSH 受体和细胞色素 P450 芳香酶的表达),而它降低了孕酮的积累水平(通过下调原代 hGL 细胞中 LH 受体和类固醇生成急性调节蛋白的表达。我们的研究结果提供了一种新的旁分泌机制,它是人类颗粒细胞中卵巢内生长因子调节的基础。我们还研究了 BMP2 对卵巢类固醇生成的影响,结果表明 BMP2 治疗显着增加了雌二醇的积累水平(通过上调 FSH 受体和细胞色素 P450 芳香酶的表达),而它降低了孕酮的积累水平(通过下调LH 受体和类固醇生成急性调节蛋白的表达)在原代 hGL 细胞中。我们的研究结果提供了一种新的旁分泌机制,它是人类颗粒细胞中卵巢内生长因子调节的基础。我们还研究了 BMP2 对卵巢类固醇生成的影响,结果表明 BMP2 治疗显着增加了雌二醇的积累水平(通过上调 FSH 受体和细胞色素 P450 芳香酶的表达),而它降低了孕酮的积累水平(通过下调LH 受体和类固醇生成急性调节蛋白的表达)在原代 hGL 细胞中。我们的研究结果提供了一种新的旁分泌机制,它是人类颗粒细胞中卵巢内生长因子调节的基础。而它降低了原代 hGL 细胞中孕酮的积累水平(通过下调 LH 受体和类固醇生成急性调节蛋白的表达)。我们的研究结果提供了一种新的旁分泌机制,它是人类颗粒细胞中卵巢内生长因子调节的基础。而它降低了原代 hGL 细胞中孕酮的积累水平(通过下调 LH 受体和类固醇生成急性调节蛋白的表达)。我们的研究结果提供了一种新的旁分泌机制,它是人类颗粒细胞中卵巢内生长因子调节的基础。
更新日期:2020-10-13
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