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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Apoptosis / drug effects*
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Bone Density Conservation Agents / chemistry
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Bone Density Conservation Agents / pharmacology*
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Bone Density Conservation Agents / therapeutic use
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Cell Line
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Cells, Cultured
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Endoplasmic Reticulum Chaperone BiP
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Endoplasmic Reticulum Stress / drug effects*
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Estradiol / chemistry
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Estradiol / pharmacology*
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Estradiol / therapeutic use
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Estrogens / chemistry
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Estrogens / pharmacology
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Estrogens / therapeutic use
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Heat-Shock Proteins / agonists*
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Heat-Shock Proteins / antagonists & inhibitors
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism
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Humans
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Mice
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Mice, Inbred C57BL
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Osteoblasts / cytology
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Osteoblasts / drug effects*
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Osteoblasts / metabolism
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Osteoporosis / chemically induced
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Osteoporosis / metabolism
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Osteoporosis / prevention & control
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Phosphorylation / drug effects
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Promoter Regions, Genetic / drug effects
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Protein Processing, Post-Translational / drug effects
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RNA Interference
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Random Allocation
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Transcription Factor TFIIA / agonists*
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Transcription Factor TFIIA / genetics
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Transcription Factor TFIIA / metabolism
Substances
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Bone Density Conservation Agents
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Endoplasmic Reticulum Chaperone BiP
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Estrogens
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HSPA5 protein, human
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Heat-Shock Proteins
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Hspa5 protein, mouse
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Recombinant Proteins
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Transcription Factor TFIIA
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Estradiol