The Antioxidant Enzyme<i>GPX1</i>Gene Polymorphisms Are Associated with Low BMD and Increased Bone Turnover Markers

Mlakar, Simona Jurković; Osredkar, Joško; Preželj, Janez; Marc, Janja

doi:10.1155/2010/354189

Cited by 27 publications

(34 citation statements)

References 46 publications

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“…In ovariectomized rats, a model of postmenopausal osteoporosis, increased levels of lipid peroxidation and H 2 O 2 and decreased levels of enzymatic antioxidants were detected in tissue homogenates from the femora (9). Furthermore, antioxidant enzyme GPX1 gene polymorphisms are associated with low bone mineral density (BMD) and increased bone turnover markers (10).…”

Section: Introductionmentioning

confidence: 99%

Simvastatin protects human osteosarcoma cells from oxidative stress-induced apoptosis through mitochondrial-mediated signaling

Zhao

Zhang

et al. 2011

Mol Med Report

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Abstract. Apoptosis of osteoblasts has been proposed as the common basis of osteoporosis, with oxidative stress as the major cause. This study was performed to investigate the protective effect of simvastatin (0.001-0.1 µM) on 100 µM hydrogen peroxide (H 2 O 2 )-mediated oxidative stress-induced apoptosis in human osteosarcoma (MG63) cells and the molecular mechanisms involved. Cell apoptosis was evaluated by observation of morphological changes and Annexin V-propidium iodide double staining followed by flow cytometric analysis. MTS assays were used to evaluate cell viability. To investigate the underlying molecular mechanisms, the expression of caspase-3, caspase-9 and Bcl-2 were analyzed by Western blotting. Following stimulation with H 2 O 2 for 24 h, a high proportion of MG63 cells underwent apoptosis, while a dosedependent inhibition of apoptosis was observed in the presence of simvastatin. A significant, dose-dependent reduction in the expression of caspase-3 and caspase-9 protein induced by H 2 O 2 in MG63 cells was observed in response to simvastatin and the Bcl-2 levels were increased. In conclusion, simvastatin protects MG63 cells from oxidative stress-induced apoptosis through downregulation of caspase-3 and caspase-9 activation and upregulation of Bcl-2 expression, suggesting a protective effect in osteoporosis. IntroductionOsteoporosis has been defined as a systemic skeletal disease characterized by gradual loss and microarchitectural deterioration of bone tissue, resulting in increased bone fragility and susceptibility to fracture (1). Osteoblasts are responsible for bone formation while osteoclasts are involved in bone resorption. Conditions such as postmenopausal osteoporosis are associated with significant changes in bone turnover; bone formation decreases and bone resorption increases or remains the same, resulting in net bone loss (2,3).Oxidative stress, resulting from excessive levels of reactive oxygen species (ROS), represents a major cause of cellular damage and death in a plethora of pathological conditions, including osteoporosis. This is associated with distinct increases in blood levels of oxidative stress markers (4-6). The main oxygen species responsible for oxidative stress are hydrogen peroxide (H 2 O 2 ), the free radical superoxide anion (O 2 -) and the hydroxyl radical (OH -). Osteoblasts produce antioxidants such as glutathione peroxidase that protect against ROS (7) and osteoclast-generated superoxide contributes to bone degradation (8). In ovariectomized rats, a model of postmenopausal osteoporosis, increased levels of lipid peroxidation and H 2 O 2 and decreased levels of enzymatic antioxidants were detected in tissue homogenates from the femora (9). Furthermore, antioxidant enzyme GPX1 gene polymorphisms are associated with low bone mineral density (BMD) and increased bone turnover markers (10).The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-COA) reductase inhibitor, simvastatin, is a widely used cholesterollowering drug that inhibits hepatic cholesterol biosynthesis. Recent...

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Section: Introductionmentioning

confidence: 99%

Simvastatin protects human osteosarcoma cells from oxidative stress-induced apoptosis through mitochondrial-mediated signaling

Zhao

Zhang

et al. 2011

Mol Med Report

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“…It is not surprising that an imbalance of protection mechanisms against oxidative stress is observed in wide range of pathologies including inflammatory and degenerative disorders with tissue fibrosis. Elevated oxidative stress was associated with low bone mineral density (Ozgocmen et al, 2007, Basu et al, 2001) and gene polymorphisms in antioxidant enzymes were also associated with low bone mineral density (Mlakar et al, 2010). Further research elucidated oxidative stress as a potential modulator of osteogenesis in different skeletal diseases (Liu et al, 2010).…”

Section: Response To Oxidative Stress -Oxidative Stress and Bonementioning

confidence: 99%

Evidence Linking Elevated Oxidative Stress and Aseptic Loosening of Hip Arthroplasty

Kinov¹,

Tivchev²

2012

Recent Advances in Arthroplasty

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“…Polymorphisms in the glutathione peroxidase 1 (GPX1) gene, which encodes an antioxidant enzyme, are associated with low bone mineral density in elderly women and men [10]. Oxidative stress is associated with increased bone resorption and low bone mass in healthy postmenopausal women [11].…”

Section: Oxidative Stress In Skeletal Physiology and Agingmentioning

confidence: 99%

“…In fact, amyotrophic lateral sclerosis, a disease of motor neuron degeneration that leads to progressive muscle wasting, results in 10% of inherited cases from mutations in the cytosolic form of the antioxidant protein superoxide dismutase (SOD1) [9]. Similar to these organs, skeletal aging and aging-related bone diseases such as osteoarthritis and metastatic bone cancers are also associated with low antioxidant defense mechanisms and ROS accumulation [3,[10][11][12].…”

Section: Introductionmentioning

confidence: 99%

FoxOs: Unifying Links Between Oxidative Stress and Skeletal Homeostasis

Kousteni

2011

Curr Osteoporos Rep

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Several mechanisms contribute to the decline of all physiologic functions during aging. As a consequence, disease incidence increases with age. Central to this multifactorial process is the increase in oxidative stress levels, which correlates with age-related disease pathogenesis in animal models and in humans. Accordingly, skeletal aging and aging-related bone diseases are also associated with accumulation of reactive oxygen species. In a variety of organs, including the skeleton, mutations in components of antioxidant defense pathways have been found to lead to progressive degenerative diseases. The molecules involved are highly conserved, can sense and respond to increases in oxidative stress levels, alterations in energy status, DNA and protein damage, and they all have a common transcriptional target, the FoxO family of Forkhead transcription factors. Oxidative stress promotes both the transcriptional activity and protein stability of FoxOs. In turn, activated FoxOs promote antioxidant defense by controlling the expression of genes involved in the oxidative stress response, DNA repair, cell cycle, and apoptosis. Among the FoxO isoforms, FoxO1 in osteoblasts uses a previously unrecognized mechanism to preserve redox balance by promoting protein synthesis and subsequently inhibiting cell cycle arrest. This evidence indicates that FoxO1 integrates and orchestrates responses to different stress signals to maintain bone cell function and preserve skeletal homeostasis.

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The Antioxidant EnzymeGPX1Gene Polymorphisms Are Associated with Low BMD and Increased Bone Turnover Markers

Cited by 27 publications

References 46 publications

Simvastatin protects human osteosarcoma cells from oxidative stress-induced apoptosis through mitochondrial-mediated signaling

Simvastatin protects human osteosarcoma cells from oxidative stress-induced apoptosis through mitochondrial-mediated signaling

Evidence Linking Elevated Oxidative Stress and Aseptic Loosening of Hip Arthroplasty

FoxOs: Unifying Links Between Oxidative Stress and Skeletal Homeostasis

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