Resveratrol rescue indoxyl sulfate-induced deterioration of osteoblastogenesis via the aryl hydrocarbon receptor /MAPK pathway

Wen Chih Liu, Jia Fwu Shyu, Yuh Feng Lin, Hui Wen Chiu, Paik Seong Lim, Chien Lin Lu, Cai Mei Zheng, Yi Chou Hou, Po Han Chen, Kuo Cheng Lu

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


Indoxyl sulfate (IS), a uremic toxin derived from dietary tryptophan metabolism by the gut microbiota, is an endogenous aryl hydrocarbon receptor (AhR) agonist and a key player in bone remodeling. Resveratrol (RSV), an AhR antagonist, plays a protective role in shielding against AhR ligands. Our study explored the impact of IS on osteoblast differentiation and examined the possible mechanism of IS in controlling the expression of osteoblastogenesis markers through an in-depth investigation of AhR signaling. In vivo, we found histological architectural disruption of the femoral bones in 5/6 nephrectomies of young adult IS exposed mice, including reduced Runx2 antigen expression. RSV improved the diaphysis architecture, Runx2 expression, and trabecular quality. In vitro data suggest that IS at 500 and 1000 µM disturbed osteoblastogenesis through suppression of the ERK and p38 mitogen-activated protein kinase (MAPK) pathways, which were found to be downstream of AhR. RSV proved to ameliorate the anti-osteoblastogenic effects of IS through the inhibition of AhR and downstream signaling. Taken together, we demonstrated that the IS/AhR/MAPK signaling pathway plays a crucial role in the inhibition of osteoblastogenesis, and RSV has a potential therapeutic role in reversing the IS-induced decline in osteoblast development and suppressing abnormal bone turnover in chronic kidney disease patients.

Original languageEnglish
Article number7483
Pages (from-to)1-23
Number of pages23
JournalInternational journal of molecular sciences
Issue number20
Publication statusPublished - Oct 2 2020


  • Aryl hydrocarbon receptor
  • Chronic kidney disease
  • Indoxyl sulfate
  • Mitogen-activated protein kinase
  • Osteoblast
  • Runx2

ASJC Scopus subject areas

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


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