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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MDPI AG
2020-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/10/3486 |
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| author | Wen-Chih Liu Jia-Fwu Shyu Paik Seong Lim Te-Chao Fang Chien-Lin Lu Cai-Mei Zheng Yi-Chou Hou Chia-Chao Wu Yuh-Feng Lin Kuo-Cheng Lu |
| author_facet | Wen-Chih Liu Jia-Fwu Shyu Paik Seong Lim Te-Chao Fang Chien-Lin Lu Cai-Mei Zheng Yi-Chou Hou Chia-Chao Wu Yuh-Feng Lin Kuo-Cheng Lu |
| author_sort | Wen-Chih Liu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T19:49:54Z |
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| id | doaj.art-b3bc05b32e2e4ffb86f2d2483d271acc |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T19:49:54Z |
| publishDate | 2020-05-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b3bc05b32e2e4ffb86f2d2483d271acc2023-11-20T00:32:07ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-05-012110348610.3390/ijms21103486Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon ReceptorWen-Chih Liu0Jia-Fwu Shyu1Paik Seong Lim2Te-Chao Fang3Chien-Lin Lu4Cai-Mei Zheng5Yi-Chou Hou6Chia-Chao Wu7Yuh-Feng Lin8Kuo-Cheng Lu9Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Biology and Anatomy, National Defense Medical Center, Taipei 114, TaiwanDivision of Nephrology, Department of Internal Medicine, Tungs’ Taichung MetroHarbor Hospital, Taichung City 435, TaiwanDivision of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, TaiwanDivision of Nephrology, Department of Medicine, Fu Jen Catholic University Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 242, TaiwanGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDivision of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, TaiwanGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDivision of Nephrology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, and School of Medicine, Buddhist Tzu Chi University, Hualien 970, TaiwanIndoxyl 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.https://www.mdpi.com/1422-0067/21/10/3486aryl hydrocarbon receptorindoxyl sulfateosteoclastchronic kidney diseaseNFATc1 |
| spellingShingle | Wen-Chih Liu Jia-Fwu Shyu Paik Seong Lim Te-Chao Fang Chien-Lin Lu Cai-Mei Zheng Yi-Chou Hou Chia-Chao Wu Yuh-Feng Lin Kuo-Cheng Lu Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor International Journal of Molecular Sciences aryl hydrocarbon receptor indoxyl sulfate osteoclast chronic kidney disease NFATc1 |
| 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 | aryl hydrocarbon receptor indoxyl sulfate osteoclast chronic kidney disease NFATc1 |
| url | https://www.mdpi.com/1422-0067/21/10/3486 |
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