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Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor

Indoxyl sulfate (IS) is a chronic kidney disease (CKD)-specific renal osteodystrophy metabolite that affects the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a transcription factor promoting osteoclastogenesis. However, the mechanisms underlying the regulation of NFATc1 by IS remain...

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Autores principales: Liu, Wen-Chih, Shyu, Jia-Fwu, Lim, Paik Seong, Fang, Te-Chao, Lu, Chien-Lin, Zheng, Cai-Mei, Hou, Yi-Chou, Wu, Chia-Chao, Lin, Yuh-Feng, Lu, Kuo-Cheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278944/
https://www.ncbi.nlm.nih.gov/pubmed/32429048
http://dx.doi.org/10.3390/ijms21103486
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author Liu, Wen-Chih
Shyu, Jia-Fwu
Lim, Paik Seong
Fang, Te-Chao
Lu, Chien-Lin
Zheng, Cai-Mei
Hou, Yi-Chou
Wu, Chia-Chao
Lin, Yuh-Feng
Lu, Kuo-Cheng
author_facet Liu, Wen-Chih
Shyu, Jia-Fwu
Lim, Paik Seong
Fang, Te-Chao
Lu, Chien-Lin
Zheng, Cai-Mei
Hou, Yi-Chou
Wu, Chia-Chao
Lin, Yuh-Feng
Lu, Kuo-Cheng
author_sort Liu, Wen-Chih
collection PubMed
description Indoxyl sulfate (IS) is a chronic kidney disease (CKD)-specific renal osteodystrophy metabolite that affects the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a transcription factor promoting osteoclastogenesis. However, the mechanisms underlying the regulation of NFATc1 by IS remain unknown. It is intriguing that the Aryl hydrocarbon receptor (AhR) plays a key role in osteoclastogenesis, since IS is an endogenous AhR agonist. This study investigates the relationship between IS concentration and osteoclast differentiation in Raw 264.7 cells, and examines the effects of different IS concentrations on NFATc1 expression through AhR signaling. Our data suggest that both osteoclastogenesis and NFATc1 are affected by IS through AhR signaling in both dose- and time-dependent manners. Osteoclast differentiation increases with short-term, low-dose IS exposure and decreases with long-term, high-dose IS exposure. Different IS levels switch the role of AhR from that of a ligand-activated transcription factor to that of an E3 ubiquitin ligase. We found that the AhR nuclear translocator may play an important role in the regulation of these dual functions of AhR under IS treatment. Altogether, this study demonstrates that the IS/AhR/NFATc1 signaling axis plays a critical role in osteoclastogenesis, indicating a potential role of AhR in the pathology and abnormality of bone turnover in CKD patients.
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spelling pubmed-72789442020-06-15 Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor Liu, Wen-Chih Shyu, Jia-Fwu Lim, Paik Seong Fang, Te-Chao Lu, Chien-Lin Zheng, Cai-Mei Hou, Yi-Chou Wu, Chia-Chao Lin, Yuh-Feng Lu, Kuo-Cheng Int J Mol Sci Article Indoxyl sulfate (IS) is a chronic kidney disease (CKD)-specific renal osteodystrophy metabolite that affects the nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a transcription factor promoting osteoclastogenesis. However, the mechanisms underlying the regulation of NFATc1 by IS remain unknown. It is intriguing that the Aryl hydrocarbon receptor (AhR) plays a key role in osteoclastogenesis, since IS is an endogenous AhR agonist. This study investigates the relationship between IS concentration and osteoclast differentiation in Raw 264.7 cells, and examines the effects of different IS concentrations on NFATc1 expression through AhR signaling. Our data suggest that both osteoclastogenesis and NFATc1 are affected by IS through AhR signaling in both dose- and time-dependent manners. Osteoclast differentiation increases with short-term, low-dose IS exposure and decreases with long-term, high-dose IS exposure. Different IS levels switch the role of AhR from that of a ligand-activated transcription factor to that of an E3 ubiquitin ligase. We found that the AhR nuclear translocator may play an important role in the regulation of these dual functions of AhR under IS treatment. Altogether, this study demonstrates that the IS/AhR/NFATc1 signaling axis plays a critical role in osteoclastogenesis, indicating a potential role of AhR in the pathology and abnormality of bone turnover in CKD patients. MDPI 2020-05-15 /pmc/articles/PMC7278944/ /pubmed/32429048 http://dx.doi.org/10.3390/ijms21103486 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Liu, Wen-Chih
Shyu, Jia-Fwu
Lim, Paik Seong
Fang, Te-Chao
Lu, Chien-Lin
Zheng, Cai-Mei
Hou, Yi-Chou
Wu, Chia-Chao
Lin, Yuh-Feng
Lu, Kuo-Cheng
Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor
title Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor
title_full Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor
title_fullStr Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor
title_full_unstemmed Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor
title_short Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor
title_sort concentration and duration of indoxyl sulfate exposure affects osteoclastogenesis by regulating nfatc1 via aryl hydrocarbon receptor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278944/
https://www.ncbi.nlm.nih.gov/pubmed/32429048
http://dx.doi.org/10.3390/ijms21103486
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