title: 17β-Estradiol inhibits ER stress-induced apoptosis through promotion of TFII-I-dependent Grp78 induction in osteoblasts.
abstract: Although many studies have suggested that estrogen prevents postmenopausal bone loss partially due to its anti-apoptosis effects in osteoblasts, the underlying mechanism has not been fully elucidated. In the present study, we found that 17β-estradiol (17β-E₂), one of the primary estrogens, inhibited endoplasmic reticulum (ER) stress-induced apoptosis in MC3T3-E1 cells and primary osteoblasts. Interestingly, 17β-E₂-promoted Grp78 induction, but not CHOP induction in response to ER stress. We further confirmed that Grp78-specific siRNA reversed the inhibition of 17β-E₂ on ER stress-induced apoptosis by activating caspase-12 and caspase-3. Moreover, we found that 17β-E₂ markedly increased the phosphorylated TFII-I levels and nuclear localization of TFII-I in ER stress conditions. 17β-E₂ stimulated Grp78 promoter activity in a dose-dependent manner in the presence of TFII-I and enhanced the binding of TFII-I to the Grp78 promoter. In addition, 17β-E₂ notably increased phosphorylated ERK1/2 levels and Ras kinase activity in MC3T3-E1 cells. The ERK1/2 activity-specific inhibitor U0126 remarkably blocked 17β-E₂-induced TFII-I phosphorylation and Grp78 expression in response to ER stress. Together, 17β-E₂ protected MC3T3-E1 cells against ER stress-induced apoptosis by promoting Ras-ERK1/2-TFII-I signaling pathway-dependent Grp78 induction.
authors.affiliation: 1] Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China [2] Cell Engineering Research Centre, Fourth Military Medical University, Xi'an, China.
authors.forename: Yun-Shan
authors.initials: YS
authors.lastname: Guo
authors.affiliation: Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Endocrinology and Metabolism, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.affiliation: Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Gao
authors.affiliation: Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Hong-Yang
authors.initials: HY
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Yue-Hu
authors.initials: YH
authors.lastname: Han
authors.affiliation: Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Hu
authors.affiliation: Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Cell Engineering Research Centre, Fourth Military Medical University, Xi'an, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Zhuo-Jing
authors.initials: ZJ
authors.lastname: Luo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004967:Estrogens / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006360:Heat-Shock Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010024:Osteoporosis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034622:RNA Interference; D011897:Random Allocation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D035561:Transcription Factor TFIIA / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
chemical_list: D050071:Bone Density Conservation Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; D004967:Estrogens; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D011994:Recombinant Proteins; D035561:Transcription Factor TFIIA; D004958:Estradiol