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

• Published in: International journal of molecular sciences Vol. 21; no. 10; p. 3486
• Main 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 15.05.2020; MDPI
• Subjects: Animals; Aromatic compounds; aryl hydrocarbon receptor; Aryl Hydrocarbon Receptor Nuclear Translocator - metabolism; Biomedical materials; Bone turnover; Cell differentiation; Cell Differentiation - drug effects; Cell Nucleus - drug effects; Cell Nucleus - metabolism; chronic kidney disease; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P-450 CYP1B1 - metabolism; Cytoplasm; Differentiation; Exposure; Gene expression; Hydrocarbons; Indican - toxicity; indoxyl sulfate; Kidney diseases; Kinases; Ligands; Metabolism; Metabolites; Mice; NFATC Transcription Factors - metabolism; NFATc1; osteoclast; Osteoclastogenesis; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteodystrophy; Osteogenesis - drug effects; Physiology; Proteins; Proto-Oncogene Proteins c-fos - metabolism; RAW 264.7 Cells; Receptors, Aryl Hydrocarbon - metabolism; Renal osteodystrophy; Signal Transduction - drug effects; Sulfates; Transcription factors; Ubiquitin; Ubiquitin-protein ligase; Ubiquitination; chronic kidney disease; NFATc1; osteoclast; indoxyl sulfate; aryl hydrocarbon receptor
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21103486

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.