Inhibition of beta‐catenin signaling by Pb leads to incomplete fracture healing

Beier, Eric E.; Sheu, Tzong‐Jen; Buckley, Taylor; Yukata, Kiminori; O’Keefe, Regis J.; Zuscik, Michael J.; Puzas, J. Edward

doi:10.1002/jor.22677

Cited by 31 publications

(18 citation statements)

References 44 publications

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“…Secondly, accumulating evidence shows a critical role for the Wnt/β-catenin signaling pathway in bone mass homeostasis [ 2 ]. Recent studies reported that toxic mechanisms of Pb on bone inhibit Wnt/β-catenin [ 37 , 38 ] signaling, and a recent phase II trial of an antagonist of schlerostin, an inhibitor of Wnt signaling, demonstrated efficacy in increasing BMD (PMID: 25196993). However, more definitive mechanisms remain largely unknown, and very few studies have examined metal exposure as a biological mechanism of osteoporosis [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Nuclear receptor and VEGF pathways for gene-blood lead interactions, on bone mineral density, in Korean smokers

Lee

Park

2018

PLoS ONE

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Osteoporosis has a complex etiology and is considered a multifactorial polygenic disease, in which genetic determinants are modulated by hormonal, lifestyle, environmental, and nutritional factors. Therefore, investigating these multiple factors, and the interactions between them, might lead to a better understanding of osteoporosis pathogenesis, and possible therapeutic interventions. The objective of this study was to identify the relationship between three blood metals (Pb, Cd, and Al), in smoking and nonsmoking patients’ sera, and prevalence of osteoporosis. In particular, we focused on gene-environment interactions of metal exposure, including a dataset obtained through genome-wide association study (GWAS). Subsequently, we conducted a pathway-based analysis, using a GWAS dataset, to elucidate how metal exposure influences susceptibility to osteoporosis. In this study, we evaluated blood metal exposures for estimating the prevalence of osteoporosis in 443 participants (aged 53.24 ± 8.29), from the Republic of Korea. Those analyses revealed a negative association between lead blood levels and bone mineral density in current smokers (p trend <0.01). By further using GWAS-based pathway analysis, we found nuclear receptor (FDR<0.05) and VEGF pathways (FDR<0.05) to be significantly upregulated by blood lead burden, with regard to the prevalence of osteoporosis, in current smokers. These findings suggest that the intracellular pathways of angiogenesis and nuclear hormonal signaling can modulate interactions between lead exposure and genetic variation, with regard to susceptibility to diminished bone mineral density. Our findings may provide new leads for understanding the mechanisms underlying the development of osteoporosis, including possible interventions.

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Section: Discussionmentioning

confidence: 99%

Nuclear receptor and VEGF pathways for gene-blood lead interactions, on bone mineral density, in Korean smokers

Lee

Park

2018

PLoS ONE

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“…Bromoindirubin oxime (BIO; Sigma Aldrich Chemicals) or control vehicle was administered intraperitoneally into 8‐week‐old wild‐type male mice (0.75 mg·kg −1 IP 3 times over 9) . Mice were sacrificed at 1 day after last BIO injection.…”

Section: Methodsmentioning

confidence: 99%

BMP3 expression by osteoblast lineage cells is regulated by canonical Wnt signaling

Kokabu

Rosen

2017

FEBS Open Bio

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Bone morphogenetic protein (BMP) and canonical Wnt (cWnt) signaling factors are both known to regulate bone mass, fracture risk, fracture repair, and osteoblastogenesis. BMP3 is the most abundant BMP and negatively regulates osteoblastogenesis and bone mass. Thus, identifying the mechanism by which BMP3 acts to depress bone formation may allow for the development of new therapeutics useful in the treatment for osteopenia and osteoporosis. Here, we report that cWnt signaling stimulates BMP3 expression in osteoblast (OB) lineage cells. The expression of BMP3 increases with OB differentiation. Treatment of cells with various cWnt proteins stimulated BMP3 expression. Mice with enhanced cWnt signaling had high expression levels of BMP3. Our data suggest that reduction in BMP3 levels may contribute beneficially to the positive effect of cWnt agonists on bone mass.

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“…BIO treatment also increased β-catenin staining to control levels ( 138 ), suggesting Wnt involvement. Indeed, BIO has been shown to induce CXCL12 expression in mouse tibial fracture callus ( 139 ). The Beier study suggests that lead may in part impact fracture repair by reducing CXCL12/CXCR4-mediated progenitor cell recruitment to the site of injury.…”

Section: Metalsmentioning

confidence: 99%

Environmental Factors Impacting Bone-Relevant Chemokines

et al. 2017

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Chemokines play an important role in normal bone physiology and the pathophysiology of many bone diseases. The recent increased focus on the individual roles of this class of proteins in the context of bone has shown that members of the two major chemokine subfamilies—CC and CXC—support or promote the formation of new bone and the remodeling of existing bone in response to a myriad of stimuli. These chemotactic molecules are crucial in orchestrating appropriate cellular homing, osteoblastogenesis, and osteoclastogenesis during normal bone repair. Bone healing is a complex cascade of carefully regulated processes, including inflammation, progenitor cell recruitment, differentiation, and remodeling. The extensive role of chemokines in these processes and the known links between environmental contaminants and chemokine expression/activity leaves ample opportunity for disruption of bone healing by environmental factors. However, despite increased clinical awareness, the potential impact of many of these environmental factors on bone-related chemokines is still ill defined. A great deal of focus has been placed on environmental exposure to various endocrine disruptors (bisphenol A, phthalate esters, etc.), volatile organic compounds, dioxins, and heavy metals, though mainly in other tissues. Awareness of the impact of other less well-studied bone toxicants, such as fluoride, mold and fungal toxins, asbestos, and chlorine, is also reviewed. In many cases, the literature on these toxins in osteogenic models is lacking. However, research focused on their effects in other tissues and cell lines provides clues for where future resources could be best utilized. This review aims to serve as a current and exhaustive resource detailing the known links between several classes of high-interest environmental pollutants and their interaction with the chemokines relevant to bone healing.

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Inhibition of beta‐catenin signaling by Pb leads to incomplete fracture healing

Cited by 31 publications

References 44 publications

Nuclear receptor and VEGF pathways for gene-blood lead interactions, on bone mineral density, in Korean smokers

Nuclear receptor and VEGF pathways for gene-blood lead interactions, on bone mineral density, in Korean smokers

BMP3 expression by osteoblast lineage cells is regulated by canonical Wnt signaling

Environmental Factors Impacting Bone-Relevant Chemokines

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