Autophagic Degradation of Collagen 1A1 by Cortisol in Human Amnion Fibroblasts.
Rupture of fetal membranes can initiate parturition at both term and preterm. Collagen is the crucial factor determining the tensile strength of the membranes. Toward the end of gestation, a feed-forward regeneration of cortisol via 11β-hydroxysteroid dehydrogenase 1 exists in fetal membranes. It remains undetermined whether cortisol contributes to collagen reduction in fetal membranes. In this study, we have examined whether cortisol accumulation is a causative factor for collagen reduction in human amnion fibroblasts, the major source of collagens in the membranes. Cortisol had no effect on collagen 1A1 (COL1A1) and 1A2 (COL1A2) messenger RNA (mRNA) abundance but decreased their protein abundance. The latter effect was affected by neither mRNA transcription inhibitor nor protein translation inhibitor. Mechanistic studies revealed that the reduction in COL1A1 but not COL1A2 protein by cortisol was blocked by lysosome inhibitor chloroquine or small interfering RNA (siRNA)-mediated knockdown of autophagy-related protein 7, an essential protein for autophagy, whereas the proteasome inhibitors MG132 and bortezomib were ineffective. Further analysis showed that cortisol dose dependently increased the ratio of LC3II/LC3I, a marker of lysosome activation, an effect blocked by the glucocorticoid receptor (GR) antagonist RU486 and siRNA-mediated knockdown of GR. Consistently, cortisol decreased COL1A1 and COL1A2 protein abundance in amnion tissue explants, and decreased COL1A1 and COL1A2 protein abundance was observed at parturition in the amnion tissue. Conclusively, cortisol regeneration in fetal membranes may contribute to rupture of fetal membranes at parturition by reducing collagen protein abundance. Lysosome-mediated autophagy accounts for the reduction in COL1A1 by cortisol, but the mechanism underlying the reduction in COL1A2 awaits further investigation.
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.|Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, P.R. China.
Yabing
Y
Mi
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.|Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, P.R. China.
Wangsheng
W
Wang
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.|Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, P.R. China.
Chuyue
C
Zhang
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.|Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, P.R. China.
Chao
C
Liu
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.|Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, P.R. China.
Jiangwen
J
Lu
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.|Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, P.R. China.
Wenjiao
W
Li
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.|Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, P.R. China.
Rujuan
R
Zuo
Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, Oregon.
Leslie
L
Myatt
Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.|Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, P.R. China.
Kang
K
Sun
D000650:Amnion / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D000069286:Bortezomib / Q000494:pharmacology; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D000090602:Collagen Type I, alpha 1 Chain; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism*; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid / Q000378:metabolism
C000601279:COL1A2 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D000069286:Bortezomib; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D006854:Hydrocortisone