title: Role of GSH/GSSG redox couple in osteogenic activity and osteoclastogenic markers of human osteoblast-like SaOS-2 cells.
abstract: This study comprised a comprehensive analysis of the glutathione (GSH) redox system during osteogenic differentiation in human osteoblast-like SaOS-2 cells. For the first time, a clear relationship between expression of specific factors involved in bone remodeling and the changes in the GSH/oxidized GSH (GSSG) redox couple induced during the early phases of the differentiation and mineralization process is shown. The findings show that the time course of differentiation is characterized by a decrease in the GSH/GSSG ratio, and this behavior is also related to the expression of osteoclastogenic markers. Maintenance of a high GSH/GSSG ratio due to GSH exposure in the early phase of this process increases mRNA levels of osteogenic differentiation markers and mineralization. Conversely, these events are decreased by a low GSH/GSSG ratio in a reversible manner. Redox regulation of runt-related transcription factor-2 (RUNX-2) activation through phosphorylation is shown. An inverse relationship between RUNX-2 activation and extracellular signal-regulated kinases related to GSH redox potential is observed. The GSH/GSSG redox couple also affects osteoclastogenesis, mainly through osteoprotegerin down-regulation with an increase in the ratio of receptor activator of NF-κB ligand to osteoprotegerin and vice versa. No redox regulation of receptor activator of NF-κB ligand expression was found. These results indicate that the GSH/GSSG redox couple may have a pivotal role in bone remodeling and bone redox-dysregulated diseases. They suggest therapeutic use of compounds that are able to modulate not just the GSH level but the intracellular redox system through the GSH/GSSG redox couple.
authors.affiliation: Department of Biochemical Science, University of Florence, Florence, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Romagnoli
authors.forename: Gemma
authors.initials: G
authors.lastname: Marcucci
authors.forename: Fabio
authors.initials: F
authors.lastname: Favilli
authors.forename: Roberto
authors.initials: R
authors.lastname: Zonefrati
authors.forename: Carmelo
authors.initials: C
authors.lastname: Mavilia
authors.forename: Gianna
authors.initials: G
authors.lastname: Galli
authors.forename: Annalisa
authors.initials: A
authors.lastname: Tanini
authors.forename: Teresa
authors.initials: T
authors.lastname: Iantomasi
authors.forename: Maria L
authors.initials: ML
authors.lastname: Brandi
authors.forename: Maria T
authors.initials: MT
authors.lastname: Vincenzini
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism* / Q000494:pharmacology; D019803:Glutathione Disulfide / Q000378:metabolism*; D006801:Humans; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D050659:Core Binding Factor Alpha 1 Subunit; D004791:Enzyme Inhibitors; D053244:Osteoprotegerin; D053245:RANK Ligand; C493709:RUNX2 protein, human; D019328:Buthionine Sulfoximine; D048049:Extracellular Signal-Regulated MAP Kinases; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D019803:Glutathione Disulfide; D000111:Acetylcysteine