title: 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.
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.
authors: Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy.
authors: Filippo
authors: F
authors: Fontani
authors: Gemma
authors: G
authors: Marcucci
authors: Teresa
authors: T
authors: Iantomasi
authors: Maria Luisa
authors: ML
authors: Brandi
authors: Maria Teresa
authors: MT
authors: Vincenzini
mesh_terms: D000111:Acetylcysteine / Q000737:chemistry*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D017209:Apoptosis; D001847:Bone Diseases / Q000378:metabolism; D016723:Bone Remodeling; D002460:Cell Line; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry*; D006023:Glycoproteins / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000737:chemistry; D036341:Intercellular Signaling Peptides and Proteins; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D009336:Necrosis; D010011:Osteocytes / Q000166:cytology; D053244:Osteoprotegerin / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D053245:RANK Ligand / Q000378:metabolism; D008063:Thioctic Acid / Q000737:chemistry*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D053244:Osteoprotegerin; D053245:RANK Ligand; C486030:Sost protein, mouse; D008063:Thioctic Acid; D006861:Hydrogen Peroxide; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; D005978:Glutathione; D000111:Acetylcysteine