TY - JOUR
T1 - Resveratrol rescue indoxyl sulfate-induced deterioration of osteoblastogenesis via the aryl hydrocarbon receptor /MAPK pathway
AU - Liu, Wen Chih
AU - Shyu, Jia Fwu
AU - Lin, Yuh Feng
AU - Chiu, Hui Wen
AU - Lim, Paik Seong
AU - Lu, Chien Lin
AU - Zheng, Cai Mei
AU - Hou, Yi Chou
AU - Chen, Po Han
AU - Lu, Kuo Cheng
N1 - Funding Information:
Funding: This research work was supported by the Ministry of Science and Technology (MOST), Taiwan (Grant no. 107-2314-B-030-001-MY3) and Tungs’ Taichung Metro Harbor Hospital, Taiwan (TTMHH-109R0021).
Funding Information:
This research work was supported by the Ministry of Science and Technology (MOST), Taiwan (Grant no. 107-2314-B-030-001-MY3) and Tungs? Taichung Metro Harbor Hospital, Taiwan (TTMHH-109R0021).
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/10/2
Y1 - 2020/10/2
N2 - 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.
AB - 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.
KW - Aryl hydrocarbon receptor
KW - Chronic kidney disease
KW - Indoxyl sulfate
KW - Mitogen-activated protein kinase
KW - Osteoblast
KW - Runx2
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U2 - 10.3390/ijms21207483
DO - 10.3390/ijms21207483
M3 - Article
C2 - 33050571
AN - SCOPUS:85092447185
SN - 1661-6596
VL - 21
SP - 1
EP - 23
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 20
M1 - 7483
ER -