Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, People's Republic of China.
J Mol Endocrinol. 2018 Feb;60(2):45-54. doi: 10.1530/JME-17-0215. Epub 2017 Nov 30.
Rupture of fetal membranes (ROM) can initiate parturition at both term and preterm. Collagen III in the compact layer of the amnion contributes to the tensile strength of fetal membranes. However, the upstream signals triggering collagen III degradation remain mostly elusive. In this study, we investigated the role of cortisol regenerated by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in collagen III degradation in human amnion fibroblasts with an aim to seek novel targets for the prevention of preterm premature ROM (pPROM)-elicited preterm birth. Human amnion tissue and cultured amnion tissue explants and amnion fibroblasts were used to study the regulation of collagen III, which is composed of three identical 3α 1 chains (COL3A1), by cortisol. Cortisol decreased COL3A1 protein but not mRNA abundance in a concentration-dependent manner. Cortisone also decreased COL3A1 protein, which was blocked by 11β-HSD1 inhibition. The reduction in COL3A1 protein by cortisol was not affected by a transcription inhibitor but was further enhanced by a translation inhibitor. Autophagic pathway inhibitor chloroquine or siRNA-mediated knock-down of ATG7, an essential protein for autophagy, failed to block cortisol-induced reduction in COL3A1 protein abundance, whereas proteasome pathway inhibitors MG132 and bortezomib significantly attenuated cortisol-induced reduction in COL3A1 protein abundance. Moreover, cortisol increased COL3A1 ubiquitination and the reduction of COL3A1 protein by cortisol was blocked by PYR-41, a ubiquitin-activating enzyme inhibitor. Conclusively, cortisol regenerated in amnion fibroblasts may be associated with ROM at parturition by reducing collagen III protein abundance through a ubiquitin-proteasome pathway.
胎膜破裂（ROM）可在足月和早产时引发分娩。羊膜致密层中的 III 型胶原有助于胎膜的拉伸强度。然而，触发 III 型胶原降解的上游信号仍然大多难以捉摸。在这项研究中，我们研究了 11β-羟类固醇脱氢酶 1（11β-HSD1）再生的皮质醇在人羊膜成纤维细胞中降解 III 型胶原的作用，旨在为预防早产胎膜早破（pPROM）引起的早产寻找新的靶点。我们使用人羊膜组织和培养的羊膜组织外植体和羊膜成纤维细胞来研究皮质醇对由三个相同的 3α1 链（COL3A1）组成的 III 型胶原的调节作用。皮质醇以浓度依赖的方式降低 COL3A1 蛋白而不降低 mRNA 丰度。皮质酮也降低 COL3A1 蛋白，这一作用可被 11β-HSD1 抑制所阻断。皮质醇对 COL3A1 蛋白的减少不受转录抑制剂的影响，但可被翻译抑制剂进一步增强。自噬途径抑制剂氯喹或 ATG7 的 siRNA 介导的敲低，ATG7 是自噬所必需的蛋白，均不能阻断皮质醇诱导的 COL3A1 蛋白丰度降低，但蛋白酶体途径抑制剂 MG132 和硼替佐米显著减弱了皮质醇诱导的 COL3A1 蛋白丰度降低。此外，皮质醇增加了 COL3A1 的泛素化，而皮质醇对 COL3A1 蛋白的减少可被 PYR-41 阻断，PYR-41 是一种泛素激活酶抑制剂。总之，在羊膜成纤维细胞中再生的皮质醇可能通过泛素蛋白酶体途径降低 COL3A1 蛋白丰度，从而与分娩时的 ROM 有关。
