Oxidative Stress Antagonizes Wnt Signaling in Osteoblast Precursors by Diverting β-Catenin from T Cell Factor- to Forkhead Box O-mediated Transcription

Almeida, Maria; Han, Li; Martin-Millan, Marta; O’Brien, Charles A.; Manolagas, Stavros C.

doi:10.1074/jbc.m702811200

Cited by 471 publications

(429 citation statements)

References 51 publications

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“…An age-related decrease in PTHrP mRNA levels in the mouse long bones is consistent with previous findings in human osteoblastic cells derived from hip and knee of elderly donors (Martinez et al 2002). It has previously been reported that a decrease in Wnt pathway activation occurs with aging (Almeida et al 2007a). Our findings here agree with this concept and demonstrate that agerelated changes in some components of this pathway, namely, β-catenin and cyclin D1 expression, in the long bones of NPAM are recapitulated in adult PAM.…”

Section: Discussionsupporting

confidence: 91%

“…Among the defensive mechanisms against oxidative stress, forkhead box O (FoxO) transcription factor family is involved in the response to ROS by driving the transcription of several antioxidant genes like catalase and growth arrest and DNA damage 45 (Gadd45) (Kops et al 2002;Tran et al 2002). In bone cells, one important effect of FoxO activation is that this transcription factor binds β-catenin to promote the expression of antioxidant gene program but avoiding that β-catenin might drive the transcription of several genes implicated in osteoblastic function (Almeida et al 2007a;Hoogeboom et al 2008). Other consequences of ROS increase include lipid peroxidation and phosphorylation of p66 Shc leading to an increase in osteoblast and osteocyte apoptosis (Trinei et al 2002;Almeida et al 2007a).…”

Section: Introductionmentioning

confidence: 99%

“…In bone cells, one important effect of FoxO activation is that this transcription factor binds β-catenin to promote the expression of antioxidant gene program but avoiding that β-catenin might drive the transcription of several genes implicated in osteoblastic function (Almeida et al 2007a;Hoogeboom et al 2008). Other consequences of ROS increase include lipid peroxidation and phosphorylation of p66 Shc leading to an increase in osteoblast and osteocyte apoptosis (Trinei et al 2002;Almeida et al 2007a).…”

Section: Introductionmentioning

confidence: 99%

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Characterization of skeletal alterations in a model of prematurely aging mice

Portal‐Núñez

Manassra

Lozano

et al. 2012

AGE

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An age-related bone loss occurs, apparently associated with the concomitant increase in an oxidative stress situation. However, the underlying mechanisms of age-related osteopenia are ill defined since these studies are time consuming and require the use of many animals (mainly rodents). Here, we aimed to characterize for the first time the bone status of prematurely aging mice (PAM), which exhibit an increased oxidative stress. Tibiae from adult (6 months) PAM show an increase in bone mineral density (BMD) and bone mineral content (assessed by bone densitometry) versus those in their normal counterparts (non-prematurely aging mice, NPAM) and similarly decreased in both kinds of mouse with age. However, at this bone site, trabecular BMD (determined by μ-computerized tomography) was similar in both adult PAM and old (18 months) NPAM. Femurs from these groups of mice present an increase in oxidative stress, inflammation, osteoclastogenic, and adipogenic markers, but a decrease in the gene expression of osteoblastic differentiation markers and of the Wnt/β-catenin pathway. Our findings show that adult PAM recapitulate various age-related bone features, and thus are a suitable model for premature bone senescence studies.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization of skeletal alterations in a model of prematurely aging mice

Portal‐Núñez

Manassra

Lozano

et al. 2012

AGE

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“…5A). Similar results were found in old mice (Cao et al ., 2003; Almeida et al ., 2007a). Inhibition of apoptosis with DEVD reversed the increase in RANKL mRNA levels, but did not change OPG mRNA levels in Cx43 def cells.…”

Section: Resultsmentioning

confidence: 99%

Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging

et al. 2017

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SummarySkeletal aging results in apoptosis of osteocytes, cells embedded in bone that control the generation/function of bone forming and resorbing cells. Aging also decreases connexin43 (Cx43) expression in bone; and osteocytic Cx43 deletion partially mimics the skeletal phenotype of old mice. Particularly, aging and Cx43 deletion increase osteocyte apoptosis, and osteoclast number and bone resorption on endocortical bone surfaces. We examined herein the molecular signaling events responsible for osteocyte apoptosis and osteoclast recruitment triggered by aging and Cx43 deficiency. Cx43‐silenced MLO‐Y4 osteocytic (Cx43def) cells undergo spontaneous cell death in culture through caspase‐3 activation and exhibit increased levels of apoptosis‐related genes, and only transfection of Cx43 constructs able to form gap junction channels reverses Cx43def cell death. Cx43def cells and bones from old mice exhibit reduced levels of the pro‐survival microRNA miR21 and, consistently, increased levels of the miR21 target phosphatase and tensin homolog (PTEN) and reduced phosphorylated Akt, whereas PTEN inhibition reduces Cx43def cell apoptosis. miR21 reduction is sufficient to induce apoptosis of Cx43‐expressing cells and miR21 deletion in miR21fl/fl bones increases apoptosis‐related gene expression, whereas a miR21 mimic prevents Cx43def cell apoptosis, demonstrating that miR21 lies downstream of Cx43. Cx43def cells release more osteoclastogenic cytokines [receptor activator of NFκB ligand (RANKL)/high‐mobility group box‐1 (HMGB1)], and caspase‐3 inhibition prevents RANKL/HMGB1 release and the increased osteoclastogenesis induced by conditioned media from Cx43def cells, which is blocked by antagonizing HMGB1‐RAGE interaction. These findings identify a novel Cx43/miR21/HMGB1/RANKL pathway involved in preventing osteocyte apoptosis that also controls osteoclast formation/recruitment and is impaired with aging.

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“…This competition inhibits the Wnt-stimulated differentiation of uncommitted mesenchymal cells into osteoblasts. The authors suggested that elevated levels of ROS in diabetes antagonize Wnt signaling and inhibits osteoblast differentiation (Almeida et al 2007). …”

Section: Discussionmentioning

confidence: 99%

Diabetes-induced fibrotic matrix inhibits intramembranous bone healing

Khosravi

Trackman

2014

J. Cell Commun. Signal.

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Diabetes diminishes bone healing and ossification. Reduced bone formation in intramembranous ossification is known, yet t he mechanism(s) behind impaired intramembranous bone healing are unclear. Here we report the formation of a fibrotic matrix during healing of intramembranous calvarial bone defects that appears to exclude new bone growth. Our histological analyses of 7-day and 14-day calvaria bone healing tissue in chemically-induced diabetic mice and non-diabetic mice showed the accumulation of a non-mineralized fibrotic matrix, likely as a consequence of unresolved hematomas under diabetic conditions. Elevated mRNA and enzyme activity levels of lysyl oxidase on day 7 in diabetic bone healing tissues also supports that the formation of a fibrotic matrix occurs in these tissues. Based on these findings, we propose that elevated fibroblast proliferation and formation of a non-mineralized fibrotic extracellular matrix in diabetes contributes to deficient intramembranous bone healing in diabetes. A greater understanding of this process has relevance to managing dental procedures in diabetics in which successful outcomes depend on intramembranous bone formation.

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Oxidative Stress Antagonizes Wnt Signaling in Osteoblast Precursors by Diverting β-Catenin from T Cell Factor- to Forkhead Box O-mediated Transcription

Cited by 471 publications

References 51 publications

Characterization of skeletal alterations in a model of prematurely aging mice

Characterization of skeletal alterations in a model of prematurely aging mice

Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging

Diabetes-induced fibrotic matrix inhibits intramembranous bone healing

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