Diminished membrane recruitment of Akt is instrumental in alcohol-associated osteopenia via the PTEN/Akt/GSK-3 beta/beta-catenin axis

Yi-Xuan Chen, Dao-Yu Zhu, Junjie Gao, Zheng-Liang Xu, Shi-Cong Tao, Wen-Jing Yin, Yue-Lei Zhang, You-Shui Gao, Chang-Qing Zhang

Research output: Contribution to journalArticle

Abstract

Alcohol is considered a leading risk factor for osteopenia. Our previous research indicated that the Akt/GSK-3 beta/beta-catenin pathway plays a critical role in the ethanol-induced antiosteogenic effect in bone mesenchymal stem cells (BMSCs). PI3K/Akt is negatively regulated by the phosphatase and tensin homolog (PTEN) phosphatase. In this study, we found that ethanol increased PTEN expression in the BMSCs and bone tissue of ethanol-treated Sprague-Dawley rats. PTEN upregulation impaired Akt recruitment to the plasma membrane and suppressed Akt phosphorylation at Ser473, thereby inhibiting Akt/GSK3 beta/beta-catenin signaling and the expression of COL1 and OCN in BMSCs in vitro and in vivo. The results of in vivo assays indicated that PTEN inhibition protected bone tissue against ethanol. Interestingly, our data revealed that following ethanol stimulation, PTEN and PTEN pseudogene 1 (PTENP1) mRNA expression was increased in a time-dependent manner, resulting in an increased PTEN protein level. In addition, ethanol upregulated PTEN expression and decreased PTEN phosphorylation (p-PTEN), indicating an increase in functional PTEN levels. In summary, the ethanol-mediated transcriptional and post-transcriptional regulation of PTEN impaired downstream Akt/GSK3 beta/beta-catenin signaling and BMSC osteogenic differentiation. Therefore, we propose that Akt/GSK3 beta/beta-catenin activation via PTEN inhibition may be a potential therapeutic approach for preventing the development of alcohol-induced osteopenia.

Original languageEnglish
Pages (from-to)1101-1119
Number of pages19
JournalFEBS Journal
Volume286
Issue number6
DOIs
Publication statusPublished - Mar 2019

Cite this

Chen, Yi-Xuan ; Zhu, Dao-Yu ; Gao, Junjie ; Xu, Zheng-Liang ; Tao, Shi-Cong ; Yin, Wen-Jing ; Zhang, Yue-Lei ; Gao, You-Shui ; Zhang, Chang-Qing. / Diminished membrane recruitment of Akt is instrumental in alcohol-associated osteopenia via the PTEN/Akt/GSK-3 beta/beta-catenin axis. In: FEBS Journal. 2019 ; Vol. 286, No. 6. pp. 1101-1119.
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title = "Diminished membrane recruitment of Akt is instrumental in alcohol-associated osteopenia via the PTEN/Akt/GSK-3 beta/beta-catenin axis",
abstract = "Alcohol is considered a leading risk factor for osteopenia. Our previous research indicated that the Akt/GSK-3 beta/beta-catenin pathway plays a critical role in the ethanol-induced antiosteogenic effect in bone mesenchymal stem cells (BMSCs). PI3K/Akt is negatively regulated by the phosphatase and tensin homolog (PTEN) phosphatase. In this study, we found that ethanol increased PTEN expression in the BMSCs and bone tissue of ethanol-treated Sprague-Dawley rats. PTEN upregulation impaired Akt recruitment to the plasma membrane and suppressed Akt phosphorylation at Ser473, thereby inhibiting Akt/GSK3 beta/beta-catenin signaling and the expression of COL1 and OCN in BMSCs in vitro and in vivo. The results of in vivo assays indicated that PTEN inhibition protected bone tissue against ethanol. Interestingly, our data revealed that following ethanol stimulation, PTEN and PTEN pseudogene 1 (PTENP1) mRNA expression was increased in a time-dependent manner, resulting in an increased PTEN protein level. In addition, ethanol upregulated PTEN expression and decreased PTEN phosphorylation (p-PTEN), indicating an increase in functional PTEN levels. In summary, the ethanol-mediated transcriptional and post-transcriptional regulation of PTEN impaired downstream Akt/GSK3 beta/beta-catenin signaling and BMSC osteogenic differentiation. Therefore, we propose that Akt/GSK3 beta/beta-catenin activation via PTEN inhibition may be a potential therapeutic approach for preventing the development of alcohol-induced osteopenia.",
keywords = "Akt/GSK3 beta/beta-catenin pathway, ethanol, hBMSCs, osteopenia, PTEN, INDUCED OSTEONECROSIS, STROMAL CELLS, BONE MASS, ACTIVATION, MTOR, GROWTH, EXPRESSION, INHIBITOR, CANCER",
author = "Yi-Xuan Chen and Dao-Yu Zhu and Junjie Gao and Zheng-Liang Xu and Shi-Cong Tao and Wen-Jing Yin and Yue-Lei Zhang and You-Shui Gao and Chang-Qing Zhang",
year = "2019",
month = "3",
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Chen, Y-X, Zhu, D-Y, Gao, J, Xu, Z-L, Tao, S-C, Yin, W-J, Zhang, Y-L, Gao, Y-S & Zhang, C-Q 2019, 'Diminished membrane recruitment of Akt is instrumental in alcohol-associated osteopenia via the PTEN/Akt/GSK-3 beta/beta-catenin axis' FEBS Journal, vol. 286, no. 6, pp. 1101-1119. https://doi.org/10.1111/febs.14754

Diminished membrane recruitment of Akt is instrumental in alcohol-associated osteopenia via the PTEN/Akt/GSK-3 beta/beta-catenin axis. / Chen, Yi-Xuan; Zhu, Dao-Yu; Gao, Junjie; Xu, Zheng-Liang; Tao, Shi-Cong; Yin, Wen-Jing; Zhang, Yue-Lei; Gao, You-Shui; Zhang, Chang-Qing.

In: FEBS Journal, Vol. 286, No. 6, 03.2019, p. 1101-1119.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Diminished membrane recruitment of Akt is instrumental in alcohol-associated osteopenia via the PTEN/Akt/GSK-3 beta/beta-catenin axis

AU - Chen, Yi-Xuan

AU - Zhu, Dao-Yu

AU - Gao, Junjie

AU - Xu, Zheng-Liang

AU - Tao, Shi-Cong

AU - Yin, Wen-Jing

AU - Zhang, Yue-Lei

AU - Gao, You-Shui

AU - Zhang, Chang-Qing

PY - 2019/3

Y1 - 2019/3

N2 - Alcohol is considered a leading risk factor for osteopenia. Our previous research indicated that the Akt/GSK-3 beta/beta-catenin pathway plays a critical role in the ethanol-induced antiosteogenic effect in bone mesenchymal stem cells (BMSCs). PI3K/Akt is negatively regulated by the phosphatase and tensin homolog (PTEN) phosphatase. In this study, we found that ethanol increased PTEN expression in the BMSCs and bone tissue of ethanol-treated Sprague-Dawley rats. PTEN upregulation impaired Akt recruitment to the plasma membrane and suppressed Akt phosphorylation at Ser473, thereby inhibiting Akt/GSK3 beta/beta-catenin signaling and the expression of COL1 and OCN in BMSCs in vitro and in vivo. The results of in vivo assays indicated that PTEN inhibition protected bone tissue against ethanol. Interestingly, our data revealed that following ethanol stimulation, PTEN and PTEN pseudogene 1 (PTENP1) mRNA expression was increased in a time-dependent manner, resulting in an increased PTEN protein level. In addition, ethanol upregulated PTEN expression and decreased PTEN phosphorylation (p-PTEN), indicating an increase in functional PTEN levels. In summary, the ethanol-mediated transcriptional and post-transcriptional regulation of PTEN impaired downstream Akt/GSK3 beta/beta-catenin signaling and BMSC osteogenic differentiation. Therefore, we propose that Akt/GSK3 beta/beta-catenin activation via PTEN inhibition may be a potential therapeutic approach for preventing the development of alcohol-induced osteopenia.

AB - Alcohol is considered a leading risk factor for osteopenia. Our previous research indicated that the Akt/GSK-3 beta/beta-catenin pathway plays a critical role in the ethanol-induced antiosteogenic effect in bone mesenchymal stem cells (BMSCs). PI3K/Akt is negatively regulated by the phosphatase and tensin homolog (PTEN) phosphatase. In this study, we found that ethanol increased PTEN expression in the BMSCs and bone tissue of ethanol-treated Sprague-Dawley rats. PTEN upregulation impaired Akt recruitment to the plasma membrane and suppressed Akt phosphorylation at Ser473, thereby inhibiting Akt/GSK3 beta/beta-catenin signaling and the expression of COL1 and OCN in BMSCs in vitro and in vivo. The results of in vivo assays indicated that PTEN inhibition protected bone tissue against ethanol. Interestingly, our data revealed that following ethanol stimulation, PTEN and PTEN pseudogene 1 (PTENP1) mRNA expression was increased in a time-dependent manner, resulting in an increased PTEN protein level. In addition, ethanol upregulated PTEN expression and decreased PTEN phosphorylation (p-PTEN), indicating an increase in functional PTEN levels. In summary, the ethanol-mediated transcriptional and post-transcriptional regulation of PTEN impaired downstream Akt/GSK3 beta/beta-catenin signaling and BMSC osteogenic differentiation. Therefore, we propose that Akt/GSK3 beta/beta-catenin activation via PTEN inhibition may be a potential therapeutic approach for preventing the development of alcohol-induced osteopenia.

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KW - ethanol

KW - hBMSCs

KW - osteopenia

KW - PTEN

KW - INDUCED OSTEONECROSIS

KW - STROMAL CELLS

KW - BONE MASS

KW - ACTIVATION

KW - MTOR

KW - GROWTH

KW - EXPRESSION

KW - INHIBITOR

KW - CANCER

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DO - 10.1111/febs.14754

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SP - 1101

EP - 1119

JO - The FEBS Journal

JF - The FEBS Journal

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