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- Title
Concentration and Duration of Indoxyl Sulfate Exposure Affects Osteoclastogenesis by Regulating NFATc1 via Aryl Hydrocarbon Receptor.
- Authors
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
- Abstract
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.
- Subjects
ARYL hydrocarbon receptors; NUCLEAR factor of activated T-cells; UBIQUITIN ligases; OSTEOCLASTOGENESIS; OSTEOCLASTS; CHRONIC kidney failure; TRANSCRIPTION factors
- Publication
International Journal of Molecular Sciences, 2020, Vol 21, Issue 10, p3486
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms21103486