Resveratrol Rescue Indoxyl Sulfate-Induced Deterioration of Osteoblastogenesis via the Aryl Hydrocarbon Receptor /MAPK Pathway

• Published in: International journal of molecular sciences Vol. 21; no. 20; p. 7483
• Main Authors: Liu, Wen-Chih, Shyu, Jia-Fwu, Lin, Yuh-Feng, Chiu, Hui-Wen, Lim, Paik Seong, Lu, Chien-Lin, Zheng, Cai-Mei, Hou, Yi-Chou, Chen, Po-Han, Lu, Kuo-Cheng
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 11.10.2020; MDPI
• Subjects: Animals; Aromatic compounds; aryl hydrocarbon receptor; Biomedical materials; Bone and Bones - diagnostic imaging; Bone and Bones - metabolism; Bone and Bones - pathology; Bone remodeling; Bone turnover; Bones; Cbfa-1 protein; Cell Differentiation; chronic kidney disease; Creatinine; Diaphysis; Downstream effects; Extracellular signal-regulated kinase; Humans; Hydrocarbons; In vivo methods and tests; Indican - adverse effects; indoxyl sulfate; Intestinal microflora; Kidney diseases; Kinases; Ligands; MAP kinase; MAP Kinase Signaling System - drug effects; Mice; Microbiota; Mineralization; mitogen-activated protein kinase; Mitogen-Activated Protein Kinases - metabolism; Models, Biological; osteoblast; Osteoblastogenesis; Osteoblasts; Osteoblasts - cytology; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteogenesis; Phosphatase; Phosphorylation; Protective Agents - pharmacology; Protein expression; Protein kinase; Proteins; Receptors, Aryl Hydrocarbon - metabolism; Renal Insufficiency, Chronic - drug therapy; Renal Insufficiency, Chronic - etiology; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - pathology; Resveratrol; Resveratrol - pharmacology; Runx2; Shielding; Signal transduction; Signal Transduction - drug effects; Surgery; Transcription factors; Tryptophan; Young adults; mitogen-activated protein kinase; chronic kidney disease; osteoblast; indoxyl sulfate; Runx2; aryl hydrocarbon receptor
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21207483

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.