Concentration and duration of indoxyl sulfate exposure affects osteoclastogenesis by regulating NFATc1 via aryl hydrocarbon receptor

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

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)


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.

Original languageEnglish
Article number3486
JournalInternational journal of molecular sciences
Issue number10
Publication statusPublished - May 2 2020


  • Aryl hydrocarbon receptor
  • Chronic kidney disease
  • Indoxyl sulfate
  • NFATc1
  • Osteoclast

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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