Role of <scp>GSH</scp>/<scp>GSSG</scp> redox couple in osteogenic activity and osteoclastogenic markers of human osteoblast‐like Sa<scp>OS</scp>‐2 cells

Romagnoli, Cecilia; Marcucci, Gemma; Favilli, Franco; Zonefrati, Roberto; Mavilia, Carmelo; Galli, Gianna; Tanini, Annalisa; Iantomasi, Teresa; Brandi, Maria Luisa; Vincenzini, Massimo

doi:10.1111/febs.12075

Cited by 60 publications

(75 citation statements)

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“…Indeed, mitogen-activated protein kinase (MAPKs) such as extracellular signal-regulated kinases (ERK1/2), c-Jun-N terminal kinase (JNK) and p38 MAPK are involved in osteoblast or osteocytes apoptosis (15,43,44). High levels of ROS block and reduce the osteoblast activity and differentiation, therefore the mineralization and osteogenesis (8,45,46) ( Figure 1). These events increase bone remodeling turnover with consequent alteration and decrease in bone mass.…”

Section: Oxidative Stress In Bone Remodelingmentioning

confidence: 99%

“…These events increase bone remodeling turnover with consequent alteration and decrease in bone mass. Antioxidants have opposing effects, they contribute to the differentiation of osteoblasts and bone formation (8,15,34,47), maintaining vital osteocytes which contribute to osteoblast activity and osteogenesis, while reduce the osteoclast differentiation and their activity ( Figure 1). There are several factors mainly produced by osteoblasts and osteocytes that regulate osteoclast and osteoblast activity and then bone remodeling, among these the most important are: the ligand of receptor activator of NF-kB (RANKL) and osteoprotegerin (OPG).…”

Section: Oxidative Stress In Bone Remodelingmentioning

confidence: 99%

“…Their expression is sensitive to increased oxidative status, that induces RANKL up-regulation and OPG down-regulation through the activation of protein kinases (ERK1/2, JNK etc.) and/or other factors which affect specific transcription factors (8,15,27). RANKL activates the differentiation and activity of osteoclasts by interacting with specific receptors in preostoeclasts and mediates osteoclastogenesis and bone resorption; while OPG, produced by the activation of the signaling pathway Wnt/βcatenin, is a soluble receptor capable of binding and blocking RANKL, resulting in inhibition of osteoclast activity (30-32, 42, 48) The oxidative stress blocks the activation of osteoblasts and thus the production of OPG; under this condition, the action of RANKL prevails, and the differentiation and activity of osteoclasts are induced.…”

Section: Oxidative Stress In Bone Remodelingmentioning

confidence: 99%

“…All these antioxidants act as direct scavengers of ROS, but they also maintain high levels of GSH, in fact, together with GSH-reductase they contribute to the elimination of GSSG formed in the reduction reactions, maintaining normal levels of GSH/GSSG and the intracellular redox state (8,14,47). Some studies relate antioxidants to bone metabolism, in fact a marked decrease in plasma antioxidants was found in aged or osteoporotic rats and in aged or osteoporotic women (17,19,38).…”

Section: Antioxidants In Bone Remodeling and In Bone Lossmentioning

confidence: 99%

“…The oxidation of GSH to GSSG and subsequent decrease in the GSH/GSSG ratio is often associated with oxidative stress. Thus, the GSH/GSSG ratio is a simple and useful indicator of cellular redox state (8,9). De novo GSH synthesis, GSSG reduction, and exogenous GSH uptake are crucial in the maintenance of cellular redox homeostasis, and GSH seems to be involved in signaling pathways being able to regulate the activity of transcription factors and protein through reactions of glutathionilation (2,10,11).…”

Section: Introductionmentioning

confidence: 99%

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Oxidative stress in bone remodeling: role of antioxidants

Domazetovic

Marcucci

Iantomasi

et al. 2017

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SummaryROS are highly reactive molecules which consist of a number of diverse chemical species, including radical and non-radical oxygen species. Oxidative stress occurs as a result of an overproduction of ROS not balanced by an adequate level of antioxidants. The natural antioxidants are: thiol compounds among which GSH is the most representative, and non-thiol compounds such as polyphenols, vitamins and also various enzymes. Many diseases have been linked to oxidative stress including bone diseases among which one of the most important is the osteoporosis. The redox state changes are also related to the bone remodeling process which allows the continuous bone regeneration through the coordinated action of bone cells: osteoclasts, osteoblasts and osteocytes. Changes in ROS and/or antioxidant systems seem to be involved in the pathogenesis of bone loss. ROS induce the apoptosis of osteoblasts and osteocytes, and this favours osteoclastogenesis and inhibits the mineralization and osteogenesis. Excessive osteocyte apoptosis correlates with oxidative stress causing an imbalance in favor of osteoclastogenesis which leads to increased turnover of bone remodeling and bone loss. Antioxidants either directly or by counteracting the action of oxidants contribute to activate the differentiation of osteoblasts, mineralization process and the reduction of osteoclast activity. In fact, a marked decrease in plasma antioxidants was found in aged or osteoporotic women. Some evidence shows a link among nutrients, antioxidant intake and bone health. Recent data demonstrate the antioxidant properties of various nutrients and their influence on bone metabolism. Polyphenols and anthocyanins are the most abundant antioxidants in the diet, and nutritional approaches to antioxidant strategies, in animals or selected groups of patients with osteoporosis or inflammatory bone diseases, suggest the antioxidant use in anti-resorptive therapies for the treatment and prevention of bone loss.

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Section: Oxidative Stress In Bone Remodelingmentioning

confidence: 99%

Section: Oxidative Stress In Bone Remodelingmentioning

confidence: 99%

Section: Oxidative Stress In Bone Remodelingmentioning

confidence: 99%

Section: Antioxidants In Bone Remodeling and In Bone Lossmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Oxidative stress in bone remodeling: role of antioxidants

Domazetovic

Marcucci

Iantomasi

et al. 2017

ccmbm

500

442

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Estrogen inhibits starvation‐induced apoptosis in osteocytes by a redox‐independent process involving association of JNK and glutathione S‐transferase P1‐1

et al. 2017

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Estrogen deficiency causes bone loss as a result of microdamage, oxidative stress, and osteocyte apoptosis. A relationship between oxidative stress‐induced apoptosis, c‐Jun N‐terminal kinase (JNK) activation, and expression of factors involved in bone remodeling has been demonstrated in osteocytes. However, the molecular regulation of these events in osteocytes treated with 17β‐estradiol (17β‐E2) remains unexplored. The MLO‐Y4 murine osteocyte‐like cell line was used as a model to study starvation‐induced apoptosis and ROS production during 17β‐E2 treatment. Expression of glutathione S‐transferase P1‐1 (GSTP1‐1), receptor activator kB ligand (RANKL), osteoprotegerin (OPG), sclerostin, and kinases activation were measured by western blot. In addition, the GSTP1‐1/JNK association was assessed by immunoprecipitation, and GSTP1‐1 involvement in the osteocyte response to 17β‐E2 was detected by specific siRNA transfection. 17β‐E2 prevents starvation‐induced apoptosis (DNA fragmentation and caspase activation), the increase in sclerostin expression and the RANKL/OPG ratio, which are all related to JNK activation due to oxidative stress in osteocytes. This occurs through GSTP1‐1 overexpression, which can inhibit JNK activation by formation of a GSTP1‐1/JNK complex. No early antioxidant action of 17β‐E2 has been found but the estrogen effect is similar to N‐acetylcysteine which, by increasing the intracellular redox state, maintains JNK bound to GSTP1‐1. Thus, the antiapoptotic and osteogenic effect of 17β‐E2 in MLO‐Y4 occurs by a redox‐independent process involving GSTP1‐1/JNK association. This study clarifies at molecular level the effect of 17β‐E2 on osteocyte activity and identifies a possible role of GSTP1‐1 and JNK activity in bone remodeling and repair mechanisms.

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Blueberry juice protects osteocytes and bone precursor cells against oxidative stress partly through SIRT1

et al. 2019

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Oxidative stress and abnormal osteocyte apoptosis are often related to dysregulation of bone turnover and chronic bone loss, and so fruit and vegetables with high antioxidant potential may play an important role in the prevention and/or management of osteoporosis. Osteocytes are the main regulators of bone remodelling. For the first time, we demonstrate here that blueberry juice ( BJ ), obtained from Vaccinium myrtillus , rich in polyphenols, shows antioxidant and antiosteoclastogenic properties in MLO ‐Y4 osteocytes. We report that BJ prevents oxidative stress‐induced apoptosis and reverses the increase in receptor activator of nuclear factor κB ligand and sclerostin expression, crucial factors for osteoclast activation and bone resorption. BJ is also able to prevent oxidative stress‐induced cell cytotoxicity in bone marrow mesenchymal stromal cells ( MSC s), which are considered to be an important tool for cell therapy in bone disorders. No significant difference in preventing these events was observed between BJ and blueberry dry extract containing equal amounts of total soluble polyphenols. We have also shown that blueberry acts as both an antioxidant and an activator of sirtuin type 1, a class III histone deacetylase involved in cell death regulation and considered a molecular target for blocking bone resorption without affecting osteoclast survival. Overall, these novel data obtained in osteocytes and MSC s may help us clarify the mechanisms by which blueberry counteracts oxidative stress‐induced damage in bone remodelling and osteogenesis at the cellular and molecular level. Our findings are consistent with the reported beneficial effects of blueberry on bone tissue reported in animal studies, which suggest that blueberry may be a useful supplement for the prevention and/or management of osteoporosis and osteogenic process.

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Role of GSH/GSSG redox couple in osteogenic activity and osteoclastogenic markers of human osteoblast‐like SaOS‐2 cells

Cited by 60 publications

References 60 publications

Oxidative stress in bone remodeling: role of antioxidants

Oxidative stress in bone remodeling: role of antioxidants

Estrogen inhibits starvation‐induced apoptosis in osteocytes by a redox‐independent process involving association of JNK and glutathione S‐transferase P1‐1

Blueberry juice protects osteocytes and bone precursor cells against oxidative stress partly through SIRT1

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