骨形态发生蛋白对非经典SMAD2/SMAD3信号的差异性激活导致永生化人颗粒细胞中透明质酸生成的不均衡诱导。

Differential activation of noncanonical SMAD2/SMAD3 signaling by bone morphogenetic proteins causes disproportionate induction of hyaluronan production in immortalized human granulosa cells.

作者信息

Zhang Han, Tian Shen, Klausen Christian, Zhu Hua, Liu Ruizhi, Leung Peter C K

机构信息

Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada; Center for Reproductive Medicine, The First Bethune Hospital, Jilin University, Changchun, Jilin, 130021, China.

Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada; Department of Reproductive Medicine, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310009, China.

出版信息

Mol Cell Endocrinol. 2016 Jun 15;428:17-27. doi: 10.1016/j.mce.2016.03.016. Epub 2016 Mar 16.

DOI:10.1016/j.mce.2016.03.016

PMID:26992562

Abstract

Successful fertilization depends upon proper cumulus-oocyte complex (COC) expansion. Synthesized by hyaluronan synthases (HASs), hyaluronan forms the backbone of the COC matrix and plays a critical role in COC expansion. This study investigated the effects and mechanisms of ovarian BMPs on HAS expression and hyaluronan production in human granulosa cells. Treatment with BMP4, BMP6, BMP7 or BMP15 induced differing levels of noncanonical SMAD2/3, but equal levels of canonical SMAD1/5/8, phosphorylation which were mirrored by differing levels of HAS2 up-regulation and hyaluronan production. The effects of BMP4 and BMP15 on HAS2 mRNA were partially reversed by knockdown of SMAD3, and blocked by knockdown of SMAD2+SMAD3 or SMAD4. BMP4-induced SMAD2/3 phosphorylation and HAS2 mRNA up-regulation were mediated by both BMP and activin/transforming growth factor-β type I receptors. Our results suggest differential activation of noncanonical SMAD2/SMAD3 signaling by BMPs causes disproportionate induction of HAS2 expression and hyaluronan production in immortalized human granulosa cells.

摘要

成功受精取决于卵丘-卵母细胞复合体（COC）的正常扩张。透明质酸由透明质酸合酶（HASs）合成，构成COC基质的主干，并在COC扩张中起关键作用。本研究调查了卵巢骨形态发生蛋白（BMPs）对人颗粒细胞中HAS表达和透明质酸产生的影响及机制。用BMP4、BMP6、BMP7或BMP15处理可诱导不同水平的非经典SMAD2/3磷酸化，但经典SMAD1/5/8磷酸化水平相同，HAS2上调水平和透明质酸产生水平的差异反映了这种情况。敲低SMAD3可部分逆转BMP4和BMP15对HAS2 mRNA的影响，敲低SMAD2+SMAD3或SMAD4可阻断这种影响。BMP4诱导的SMAD2/3磷酸化和HAS2 mRNA上调由BMP和激活素/转化生长因子-β I型受体介导。我们的结果表明，BMPs对非经典SMAD2/SMAD3信号的差异激活导致永生化人颗粒细胞中HAS2表达和透明质酸产生的诱导不成比例。