Glucocorticoids and Tumor Necrosis Factor α Increase Oxidative Stress and Suppress Wnt Protein Signaling in Osteoblasts

Almeida, Maria; Han, Li; Ambrogini, Elena; Weinstein, Robert S.; Manolagas, Stavros C.

doi:10.1074/jbc.m111.283481

Cited by 238 publications

(190 citation statements)

References 72 publications

(46 reference statements)

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“…Our study showed that Dex led to excessive ROS generation and increased MDA, whereas it inhibited the activity of SOD, GSH, and CAT in larval zebrafish, consistent with reports that GC is an oxidant stimulus that triggers ROS generation and activates OS in bone [13] . Sal B hampered the increase in ROS generation and MDA levels; however, it did not significantly increase the activities of these antioxidant enzymes.…”

Section: Discussionsupporting

confidence: 78%

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Salvianolic acid B stimulates osteogenesis in dexamethasone-treated zebrafish larvae

et al. 2016

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Aim: Our previous studies show that salvianolic acid B (Sal B) promotes osteoblast differentiation and matrix mineralization. In this study, we evaluated the protective effects of Sal B on the osteogenesis in dexamethasone (Dex)-treated larval zebrafish, and elucidated the underlying mechanisms. Methods: At 3 d post fertilization, wild-type AB zebrafish larvae or bone transgenic tg (sp7:egfp) zebrafish larvae were exposed to Sal B, Dex, or a mixture of Dex+Sal B for 6 d. Bone mineralization in AB strain larval zebrafish was assessed with alizarin red staining, and osteoblast differentiation in tg (sp7:egfp) larval zebrafish was examined with fluorescence scanning. The expression of osteoblastspecific genes in the larvae was detected using qRT-PCR assay. The levels of oxidative stress markers (ROS and MDA) in the larvae were also measured. Results: Exposure to Dex (5-20 μmol/L) dose-dependently decreased the bone mineralization area and integral optical density (IOD) in wild-type AB zebrafish larvae and the osteoblast fluorescence area and IOD in tg (sp7:egfp) zebrafish larvae. Exposure to Dex (10 μmol/L) significantly reduced the expression of osteoblast-specific genes, including runx2a, osteocalcin (OC), alkaline phosphatase (ALP) and osterix (sp7), and increased the accumulation of ROS and MDA in the larvae. Co-exposure to Sal B (0.2-2 μmol/L) dosedependently increased the bone mineralization area and IOD in AB zebafish larvae and osteoblast fluorescence in tg (sp7:egfp) zebrafish larvae. Co-exposure to Sal B (2 μmol/L) significantly attenuated deleterious alterations in bony tissue and oxidative stress in both Dex-treated AB zebafish larvae and tg (sp7:egfp) zebrafish larvae. Conclusion: Sal B stimulates bone formation and rescues GC-caused inhibition on osteogenesis in larval zebrafish by counteracting oxidative stress and increasing the expression of osteoblast-specific genes. Thus, Sal B may have protective effects on bone loss trigged by GC.

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Section: Discussionsupporting

confidence: 78%

“…Furthermore, studies confirm that GC elicits increased ROS production and subsequent OS in skeletal tissue [11][12][13] . These studies indicate that excessive GC may significantly contribute to bone loss, partially due to oxidative stress, and antioxidant treatment may counteract GC-induced osteopenia and osteoporosis.…”

Section: Introductionmentioning

confidence: 48%

Salvianolic acid B stimulates osteogenesis in dexamethasone-treated zebrafish larvae

et al. 2016

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“…However, glucocorticoids might regulate some of these genes by interfering with the Wnt/b-catenin pathway itself, whereas they might control other genes either directly by repressing the activity of their promoters or through regulation of alternative pathways including kinase signaling or induction of ROS/ endoplasmic reticulum (ER) stress. (31,49,(64)(65)(66)(67) In closing, the current report demonstrates that the deleterious effects of glucocorticoids on the skeleton are linked to increased expression of the osteocyte-derived Wnt/b-catenin antagonist Sost/sclerostin and to downregulation of Wnt/bcatenin target genes; and that Sost/sclerostin deficiency prevents glucocorticoid-induced osteoporosis by anti-catabolic, not anabolic, actions.…”

Section: Discussionmentioning

confidence: 53%

Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

Sato

Cregor

Delgado‐Calle

et al. 2016

Journal of Bone and Mineral Research

100

108

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Excess of glucocorticoids, either due to disease or iatrogenic, increases bone resorption and decreases bone formation and is a leading cause of osteoporosis and bone fractures worldwide. Improved therapeutic strategies are sorely needed. We investigated whether activating Wnt/b-catenin signaling protects against the skeletal actions of glucocorticoids, using female mice lacking the Wnt/b-catenin antagonist and bone formation inhibitor Sost. Glucocorticoids decreased the mass, deteriorated the microarchitecture, and reduced the structural and material strength of bone in wild-type (WT), but not in Sost -/-mice. The high bone mass exhibited by Sost -/-mice is due to increased bone formation with unchanged resorption. However, unexpectedly, preservation of bone mass and strength in Sost -/-mice was due to prevention of glucocorticoid-induced bone resorption and not to restoration of bone formation. In WT mice, glucocorticoids increased the expression of Sost and the number of sclerostin-positive osteocytes, and altered the molecular signature of the Wnt/b-catenin pathway by decreasing the expression of genes associated with both anticatabolism, including osteoprotegerin (OPG), and anabolism/survival, such as cyclin D1. In contrast in Sost -/-mice, glucocorticoids did not decrease OPG but still reduced cyclin D1. Thus, in the context of glucocorticoid excess, activation of Wnt/b-catenin signaling by Sost/sclerostin deficiency sustains bone integrity by opposing bone catabolism despite markedly reduced bone formation and increased apoptosis. This crosstalk between glucocorticoids and Wnt/b-catenin signaling could be exploited therapeutically to halt resorption and bone loss induced by glucocorticoids and to inhibit the exaggerated bone formation in diseases of unwanted hyperactivation of Wnt/b-catenin signaling.

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“…For example, it is known that reactive oxygen species stimulate pro-inflammatory cytokine production through activation of intracellular signalling pathways such as MAP kinase, NF-jB and the NALP3 inflammasome (Graves & Kayal 2008, Martinon 2010. Reactive oxygen species also have more wide ranging effects including effects on bone formation and recently revealed pathways involving the interaction of reactive oxygen species, Wnt signalling and activation of FoxO transcription factors in the regulation of osteoblast activity suggest another novel pathway which may link periodontitis and diabetes (Almeida et al 2011, Galli et al 2011. Hyperleptinaemia, a condition also associated with diabetes and obesity, can also promote oxidative stress which may exacerbate the effect of hyperglycaemia in promoting a proinflammatory state (Bullon et al 2009).…”

Section: Hyperglycaemia and Cellular Stressmentioning

confidence: 99%

A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes

Taylor

Preshaw

Lalla

2013

Journal of Periodontology

204

256

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A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes Taylor JJ, Preshaw PM, Lalla E. A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes.Abstract Aims: To review the evidence for the molecular and cellular processes that may potentially link periodontal disease and diabetes. The pathogenic roles of cytokines and metabolic molecules (e.g. glucose, lipids) are explored and the role of periodontal bacteria is also addressed. Paradigms for bidirectional relationships between periodontitis and diabetes are discussed and opportunities for elaborating these models are considered. Methods: Database searches were performed using MeSH terms, keywords, and title words. Studies were evaluated and summarized in a narrative review. Results: Periodontal microbiota appears unaltered by diabetes and there is little evidence that it may influence glycaemic control. Small-scale clinical studies and experiments in animal models suggest that IL-1b, TNF-a, IL-6, OPG and RANKL may mediate periodontitis in diabetes. The AGE-RAGE axis is likely an important pathway of tissue destruction and impaired repair in diabetesassociated periodontitis. A role for locally activated pro-inflammatory factors in the periodontium, which subsequently impact on diabetes, remains speculative. Conclusion: There is substantial information on potential mechanistic pathways which support a close association between diabetes and periodontitis, but there is a real need for longitudinal clinical studies using larger patient groups, integrated with studies of animal models and cells/tissues in vitro.

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Glucocorticoids and Tumor Necrosis Factor α Increase Oxidative Stress and Suppress Wnt Protein Signaling in Osteoblasts

Cited by 238 publications

References 72 publications

Salvianolic acid B stimulates osteogenesis in dexamethasone-treated zebrafish larvae

Salvianolic acid B stimulates osteogenesis in dexamethasone-treated zebrafish larvae

Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

A review of the evidence for pathogenic mechanisms that may link periodontitis and diabetes

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