Aryl Hydrocarbon Receptor Antagonists Mitigate the Effects of Dioxin on Critical Cellular Functions in Differentiating Human Osteoblast-Like Cells
AbstractThe 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
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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.
Yun C, Katchko KM, Schallmo MS, Jeong S, Yun J, Chen CH, Weiner JA, Park C, George A, Stupp SI, Hsu WK, Hsu EL. Aryl Hydrocarbon Receptor Antagonists Mitigate the Effects of Dioxin on Critical Cellular Functions in Differentiating Human Osteoblast-Like Cells. International Journal of Molecular Sciences. 2018; 19(1):225.Chicago/Turabian Style
Yun, Chawon; Katchko, Karina M.; Schallmo, Michael S.; Jeong, Soyeon; Yun, Jonghwa; Chen, Charlotte H.; Weiner, Joseph A.; Park, Christian; George, Andrew; Stupp, Samuel I.; Hsu, Wellington K.; Hsu, Erin L. 2018. "Aryl Hydrocarbon Receptor Antagonists Mitigate the Effects of Dioxin on Critical Cellular Functions in Differentiating Human Osteoblast-Like Cells." Int. J. Mol. Sci. 19, no. 1: 225.
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