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Glutathione, N-acetylcysteine and Lipoic Acid Down-Regulate Starvation-Induced Apoptosis, RANKL/OPG Ratio and Sclerostin in Osteocytes: Involvement of JNK and ERK1/2 Signalling

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Abstract

Osteocyte apoptosis due to microdamage and/or oxidative stress is related to increased local bone turnover and resorption observed in various bone diseases. Previous data on osteoblasts and osteoclasts have linked reactive oxygen species and antioxidants to bone remodelling. This study performs a comprehensive analysis on the effect of antioxidants such as glutathione (GSH), N-acetylcysteine and lipoic acid (LA) on starvation-induced osteocyte apoptosis and on cytokines involved in bone remodelling such as the receptor activator kB ligand (RANKL), osteoprotegerin (OPG) and sclerostin. For this study, apoptosis was induced by serum starvation in a murine osteocyte-like cell line MLO-Y4; this condition mimics in part osteocyte apoptosis due to microdamage. The results show that starvation-induced apoptosis and expression of RANKL, OPG and sclerostin are redox regulated processes. All antioxidants are able to inhibit the apoptosis due to starvation. They down-regulate the expression and the release of RANKL, the expression of sclerostin and RANKL/OPG ratio, whereas they only in part up-regulate OPG expression. Antioxidants mediate their effect on starvation-induced apoptosis by JNK signalling and on cytokine expression by both JNK and ERK1/2 activities. This study shows the possible involvement of biological antioxidants such as GSH and LA on redox regulated mechanisms related to apoptosis and expression of cytokines involved in bone remodelling. Moreover, it suggests that both JNK and ERK1/2 may be useful biological targets for drugs affecting bone diseases associated with increased oxidative stress.

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Acknowledgments

We would like to thank Dr. Lynda Bonewald for the MLO-Y4 cells and the careful reading and review of the manuscript. This study was supported by grants from the Ministero dell’Istruzione, dell’Università e della Ricerca and Fondazione Cassa di Risparmio di Firenze.

Conflict of interest

Vincenzini, Fontani, Marcucci, Iantomasi, Brandi have nothing to disclose.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy

    Filippo Fontani, Teresa Iantomasi & Maria Teresa Vincenzini

  2. Department of Surgery and Translational Medicine, Bone Metabolic Diseases Unit, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy

    Gemma Marcucci & Maria Luisa Brandi

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  1. Filippo Fontani
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  2. Gemma Marcucci
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  5. Maria Teresa Vincenzini
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Correspondence to Maria Teresa Vincenzini.

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Fontani, F., Marcucci, G., Iantomasi, T. et al. Glutathione, N-acetylcysteine and Lipoic Acid Down-Regulate Starvation-Induced Apoptosis, RANKL/OPG Ratio and Sclerostin in Osteocytes: Involvement of JNK and ERK1/2 Signalling. Calcif Tissue Int 96, 335–346 (2015). https://doi.org/10.1007/s00223-015-9961-0

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  • DOI: https://doi.org/10.1007/s00223-015-9961-0

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