Mechanistic insight into the effects of Aryl Hydrocarbon Receptor activation on osteogenic differentiation

Yun, Chawon; Weiner, Joseph A.; Chun, Danielle S.; Yun, Jonghwa; Cook, Ralph W.; Schallmo, Michael S.; Kannan, Abhishek; Mitchell, Sean M.; Freshman, Ryan D.; Park, Christian; Hsu, Wellington K.; Hsu, Erin L.

doi:10.1016/j.bonr.2017.02.003

Cited by 16 publications

(19 citation statements)

References 43 publications

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“…[ 44 ] Also, one of the mediators of the anti-osteogenic effects of cigarette smoking, the aryl hydrocarbon receptor, can adversely affect bone regeneration and bone healing. [ 45 ] Thus, the benefit of tea consumption is likely to be offset significantly by these bad habits in male. This could, however, explain why tea consumption can significantly reduce the risk of OP in female population but not in males.…”

Section: Discussionmentioning

confidence: 99%

Association between tea consumption and osteoporosis

Sun¹,

Wang²,

Ma³

et al. 2017

Medicine

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Section: Discussionmentioning

confidence: 99%

Association between tea consumption and osteoporosis

Sun¹,

Wang²,

Ma³

et al. 2017

Medicine

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“…Since the effects of dioxin on bone formation are likely mediated at least in part by the AhR [ 12 ], we hypothesized that co-treatment with dioxin and the AhR antagonists ANF, resveratrol, or DIM could prevent the dioxin-mediated inhibition of osteogenic differentiation. In preliminary work, we showed that at the relevant time points, cell proliferation was not inhibited by 0.5 µM ANF, 4 µM Res, and 10 μM DIM, and we subsequently used these doses for co-treatment studies.…”

Section: Resultsmentioning

confidence: 99%

“…While it has been posited that a number of constituents of cigarette smoke—including nicotine—may play a role in the smoking-mediated inhibition of bone healing, the role of the aryl hydrocarbon receptor (AhR) has become a recent focus of active research [ 35 , 36 ]. The AhR is responsible for regulating xenobiotic metabolism and mediating the toxicity of environmental planar aromatic hydrocarbons, with previous studies suggesting deleterious effects of AhR hyper-activation on bone biology [ 12 , 13 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…Because of its extremely high affinity for the receptor, dioxin is frequently used as a prototypical ligand to investigate the effects of the AhR pathway involvement in biological processes. Previous in vitro studies have shown that dioxin inhibits osteoblastic differentiation and ALP activity in murine cell lines and have also identified dioxin-sensitive proteins that are critical mediators of osteogenesis [ 12 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD, referred herein as “dioxin”) has the highest affinity for the AhR and has been shown to adversely affect bone [ 10 , 11 ]. Downstream effects of AhR activation by ligands such as dioxin include inhibition of osteoblast differentiation, function, and reduced ossification [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Aryl Hydrocarbon Receptor Antagonists Mitigate the Effects of Dioxin on Critical Cellular Functions in Differentiating Human Osteoblast-Like Cells

Yun

Katchko

Schallmo

et al. 2018

IJMS

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The inhibition of bone healing in humans is a well-established effect associated with cigarette smoking, but the underlying mechanisms are still unclear. Recent work using animal cell lines have implicated the aryl hydrocarbon receptor (AhR) as a mediator of the anti-osteogenic effects of cigarette smoke, but the complexity of cigarette smoke mixtures makes understanding the mechanisms of action a major challenge. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a high-affinity AhR ligand that is frequently used to investigate biological processes impacted by AhR activation. Since there are dozens of AhR ligands present in cigarette smoke, we utilized dioxin as a prototype ligand to activate the receptor and explore its effects on pro-osteogenic biomarkers and other factors critical to osteogenesis using a human osteoblast-like cell line. We also explored the capacity for AhR antagonists to protect against dioxin action in this context. We found dioxin to inhibit osteogenic differentiation, whereas co-treatment with various AhR antagonists protected against dioxin action. Dioxin also negatively impacted cell adhesion with a corresponding reduction in the expression of integrin and cadherin proteins, which are known to be involved in this process. Similarly, the dioxin-mediated inhibition of cell migration correlated with reduced expression of the chemokine receptor CXCR4 and its ligand, CXCL12, and co-treatment with antagonists restored migratory capacity. Our results suggest that AhR activation may play a role in the bone regenerative response in humans exposed to AhR activators, such as those present in cigarette smoke. Given the similarity of our results using a human cell line to previous work done in murine cells, animal models may yield data relevant to the human setting. In addition, the AhR may represent a potential therapeutic target for orthopedic patients who smoke cigarettes, or those who are exposed to secondhand smoke or other environmental sources of aryl hydrocarbons.

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Effects of cigarette smoke condensate on proliferation and pluripotency gene expression in mouse embryonic stem cells

Assadollahi

Mohammadi

Fathi

et al. 2018

J of Cellular Biochemistry

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Background: Embryonic stem cells (ESCs) are derived from the inner cell mass (ICM) of blastocysts. They can be used as valuable experimental models to test the effects of drugs, chemicals, and environmental contaminants such as cigarette smoke condensate (CSC) on preimplantation embryo development.The aim of this study was to evaluate the effect of CSC on ESCs derived from mice with different genetic backgrounds and maternal ages. Methods:The study groups consisted of mouse ESCs (mESCs) obtained from three sources: blastocysts developed from fertilized oocytes of two-month-old (2-C57) and six-month-old (6-C57) C57BL/6 inbred mice and those developed from fertilized oocytes of two-month-old (2-NMRI) NMRI outbred mice. The groups of mESCs were exposed to 0.04, 4, and 40 μg/mL CSC. After exposure, we measured cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and real-time polymerase chain reaction for changes in expressions of Oct4, Sox2, Nanog, Ahr, Bax, Bcl2, TFAM, and POLG. The cell doubling time (DT) of these populations was also determined.Results: We observed that CSC changed proliferation and DT in the 2-C57 and 6-C57 cells. There was no change in 2-NMRI cells. Exposure to CSC caused changes in the gene expressions and induced apoptosis in all three cell lines.Conclusion: Based on the results of the study, it can be concluded that CSC has an effect on the viability, DT and gene expression patterns in mouse ESCs and its effects vary based on the genetic background and maternal age of isolated mouse ESCs.

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Mechanistic insight into the effects of Aryl Hydrocarbon Receptor activation on osteogenic differentiation

Cited by 16 publications

References 43 publications

Association between tea consumption and osteoporosis

Association between tea consumption and osteoporosis

Aryl Hydrocarbon Receptor Antagonists Mitigate the Effects of Dioxin on Critical Cellular Functions in Differentiating Human Osteoblast-Like Cells

Effects of cigarette smoke condensate on proliferation and pluripotency gene expression in mouse embryonic stem cells

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