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

While inhibition of bone healing and increased rates of pseudarthrosis are known adverse outcomes associated with cigarette smoking, the underlying mechanisms by which this occurs are not well understood. Recent work has implicated the Aryl Hydrocarbon Receptor (Ahr) as one mediator of the anti-oste...

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Autores principales: Yun, Chawon, Weiner, Joseph A., Chun, Danielle S., Yun, Jonghwa, Cook, Ralph W., Schallmo, Michael S., Kannan, Abhishek S., Mitchell, Sean M., Freshman, Ryan D., Park, Christian, Hsu, Wellington K., Hsu, Erin L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365310/
https://www.ncbi.nlm.nih.gov/pubmed/28377982
http://dx.doi.org/10.1016/j.bonr.2017.02.003
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author Yun, Chawon
Weiner, Joseph A.
Chun, Danielle S.
Yun, Jonghwa
Cook, Ralph W.
Schallmo, Michael S.
Kannan, Abhishek S.
Mitchell, Sean M.
Freshman, Ryan D.
Park, Christian
Hsu, Wellington K.
Hsu, Erin L.
author_facet Yun, Chawon
Weiner, Joseph A.
Chun, Danielle S.
Yun, Jonghwa
Cook, Ralph W.
Schallmo, Michael S.
Kannan, Abhishek S.
Mitchell, Sean M.
Freshman, Ryan D.
Park, Christian
Hsu, Wellington K.
Hsu, Erin L.
author_sort Yun, Chawon
collection PubMed
description While inhibition of bone healing and increased rates of pseudarthrosis are known adverse outcomes associated with cigarette smoking, the underlying mechanisms by which this occurs are not well understood. Recent work has implicated the Aryl Hydrocarbon Receptor (Ahr) as one mediator of the anti-osteogenic effects of cigarette smoke (CS), which contains numerous toxic ligands for the Ahr. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a high-affinity Ahr ligand frequently used to evaluate Ahr pathway activation. The purpose of this study was to elucidate the downstream mechanisms of dioxin action on bone regeneration and investigate Ahr antagonism as a potential therapeutic approach to mitigate the effects of dioxin on bone. Markers of osteogenic activity and differentiation were assessed in primary rat bone marrow stromal cells (BMSC) after exposure to dioxin, Ahr antagonists, or antagonist + dioxin. Four Ahr antagonists were evaluated: α-Naphthoflavone (ANF), resveratrol (Res), 3,3′-Diindolylmethane (DIM), and luteolin (Lut). Our results demonstrate that dioxin inhibited ALP activity, migratory capacity, and matrix mineralization, whereas co-treatment with each of the antagonists mitigated these effects. Dioxin also inhibited BMSC chemotaxis, while co-treatment with several antagonists partially rescued this effect. RNA and protein expression studies found that dioxin down-regulated numerous pro-osteogenic targets, whereas co-treatment with Ahr antagonists prevented these dioxin-induced expression changes to varying degrees. Our results suggest that dioxin adversely affects bone regeneration in a myriad of ways, many of which appear to be mediated by the Ahr. Our work suggests that the Ahr should be investigated as a therapeutic target to combat the adverse effects of CS on bone healing.
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spelling pubmed-53653102017-04-04 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 S. Mitchell, Sean M. Freshman, Ryan D. Park, Christian Hsu, Wellington K. Hsu, Erin L. Bone Rep Article While inhibition of bone healing and increased rates of pseudarthrosis are known adverse outcomes associated with cigarette smoking, the underlying mechanisms by which this occurs are not well understood. Recent work has implicated the Aryl Hydrocarbon Receptor (Ahr) as one mediator of the anti-osteogenic effects of cigarette smoke (CS), which contains numerous toxic ligands for the Ahr. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) is a high-affinity Ahr ligand frequently used to evaluate Ahr pathway activation. The purpose of this study was to elucidate the downstream mechanisms of dioxin action on bone regeneration and investigate Ahr antagonism as a potential therapeutic approach to mitigate the effects of dioxin on bone. Markers of osteogenic activity and differentiation were assessed in primary rat bone marrow stromal cells (BMSC) after exposure to dioxin, Ahr antagonists, or antagonist + dioxin. Four Ahr antagonists were evaluated: α-Naphthoflavone (ANF), resveratrol (Res), 3,3′-Diindolylmethane (DIM), and luteolin (Lut). Our results demonstrate that dioxin inhibited ALP activity, migratory capacity, and matrix mineralization, whereas co-treatment with each of the antagonists mitigated these effects. Dioxin also inhibited BMSC chemotaxis, while co-treatment with several antagonists partially rescued this effect. RNA and protein expression studies found that dioxin down-regulated numerous pro-osteogenic targets, whereas co-treatment with Ahr antagonists prevented these dioxin-induced expression changes to varying degrees. Our results suggest that dioxin adversely affects bone regeneration in a myriad of ways, many of which appear to be mediated by the Ahr. Our work suggests that the Ahr should be investigated as a therapeutic target to combat the adverse effects of CS on bone healing. Elsevier 2017-02-16 /pmc/articles/PMC5365310/ /pubmed/28377982 http://dx.doi.org/10.1016/j.bonr.2017.02.003 Text en © 2017 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Yun, Chawon
Weiner, Joseph A.
Chun, Danielle S.
Yun, Jonghwa
Cook, Ralph W.
Schallmo, Michael S.
Kannan, Abhishek S.
Mitchell, Sean M.
Freshman, Ryan D.
Park, Christian
Hsu, Wellington K.
Hsu, Erin L.
Mechanistic insight into the effects of Aryl Hydrocarbon Receptor activation on osteogenic differentiation
title Mechanistic insight into the effects of Aryl Hydrocarbon Receptor activation on osteogenic differentiation
title_full Mechanistic insight into the effects of Aryl Hydrocarbon Receptor activation on osteogenic differentiation
title_fullStr Mechanistic insight into the effects of Aryl Hydrocarbon Receptor activation on osteogenic differentiation
title_full_unstemmed Mechanistic insight into the effects of Aryl Hydrocarbon Receptor activation on osteogenic differentiation
title_short Mechanistic insight into the effects of Aryl Hydrocarbon Receptor activation on osteogenic differentiation
title_sort mechanistic insight into the effects of aryl hydrocarbon receptor activation on osteogenic differentiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365310/
https://www.ncbi.nlm.nih.gov/pubmed/28377982
http://dx.doi.org/10.1016/j.bonr.2017.02.003
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