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4-Phenyl butyric acid prevents glucocorticoid-induced osteoblast apoptosis by attenuating endoplasmic reticulum stress

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Abstract

Apoptosis of osteoblasts triggered by high-dose glucocorticoids (GCs) has been identified as a major cause of osteoporosis. However, the molecular mechanisms underlying GC-induced osteoporosis remain elusive. This study was conducted to make clear the mechanism of GC-induced osteoblast apoptosis and to examine whether reduction of ER stress by 4-PBA inhibited osteoblast apoptosis. After treatment with dexamethasone (Dex) or hydrocortisone, cell viability was assessed using an MTT assay. Flow cytometry was performed to assess the apoptosis of MC3T3-E1 cells. The expression levels of ER stress-related proteins (CHOP, GRP78, eIF2α, and phospho-eIF2α) and apoptosis-related proteins (cleaved Caspase-3, Bcl-2, and Bax) in MC3T3-E1 cells were measured by Western blot analysis. We found that both Dex and hydrocortisone reduced cell proliferation and promoted apoptosis in MC3T3-E1 cells. In addition, the protein expression levels of cleaved Caspase-3 and Bax increased and the protein expression level of Bcl-2 decreased in MC3T3-E1 cells exposed to Dex. In addition, the Dex exposure also resulted in a release of cytochrome c (Cyt C) from mitochondria. The cellular ATP content was decreased following prolonged treatment with Dex. 4-PBA attenuated ER stress and mitochondrial dysfunction induced by Dex in MC3T3-E1 cells. Dex-mediated apoptosis of MC3T3-E1 cells is aggravated by ER stress. Moreover, Dex-induced apoptosis in MC3T3-E1 cells was inhibited by 4-PBA, suggesting that ER stress involved in Dex-induced apoptosis. In conclusion, inhibition of ER stress by 4-PBA could reduce GC-induced apoptosis in MC3T3-E1 cells.

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Acknowledgments

This work was funded by the Natural Science Foundation of Shaanxi Province (Grant No. 2014JM4193).

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    Authors and Affiliations

    1. Rehabilitation Center, The First Affiliated Hospital of Health Science Center, Xi’an Jiaotong University, No 277 Yanta West Road, Xi’an, 710061, Shaanxi Province, China

      Jianhui Yang, Qiong Wu, Jianguo Lv & Huiyong Nie

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    1. Jianhui Yang
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    2. Qiong Wu
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    3. Jianguo Lv
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    Correspondence to Jianhui Yang.

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    J. Yang and Q. Wu contributed equally to this work.

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    Yang, J., Wu, Q., Lv, J. et al. 4-Phenyl butyric acid prevents glucocorticoid-induced osteoblast apoptosis by attenuating endoplasmic reticulum stress. J Bone Miner Metab 35, 366–374 (2017). https://doi.org/10.1007/s00774-016-0778-3

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    • DOI: https://doi.org/10.1007/s00774-016-0778-3

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