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Int. J. Mol. Sci. 2018, 19(1), 225; https://doi.org/10.3390/ijms19010225

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

1
Department of Orthopaedic Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
2
Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, IL 60611, USA
3
Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, USA
4
Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA
5
Department of Chemistry, Northwestern University, Evanston, IL 60208, USA
6
Department of Medicine, Northwestern University, Chicago, IL 60611, USA
*
Author to whom correspondence should be addressed.
Received: 10 November 2017 / Revised: 20 December 2017 / Accepted: 10 January 2018 / Published: 11 January 2018
(This article belongs to the Special Issue Aryl Hydrocarbon Receptor in Biology and Toxicology)
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Abstract

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. View Full-Text
Keywords: TCDD; dioxin; bone healing; smoking; aryl hydrocarbon receptor TCDD; dioxin; bone healing; smoking; aryl hydrocarbon receptor
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Yun, C.; Katchko, K.M.; Schallmo, M.S.; Jeong, S.; Yun, J.; Chen, C.H.; Weiner, J.A.; Park, C.; George, A.; Stupp, S.I.; Hsu, W.K.; Hsu, E.L. Aryl Hydrocarbon Receptor Antagonists Mitigate the Effects of Dioxin on Critical Cellular Functions in Differentiating Human Osteoblast-Like Cells. Int. J. Mol. Sci. 2018, 19, 225.

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