Resveratrol Rescue Indoxyl Sulfate-Induced Deterioration of Osteoblastogenesis via the Aryl Hydrocarbon Receptor /MAPK Pathway
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 stu...
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MDPI AG
2020-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/20/7483 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Wen-Chih Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T15:43:10Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T15:43:10Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-1aa648117a28430f93fe9f2884c25f7f2023-11-20T16:37:08ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-012120748310.3390/ijms21207483Resveratrol Rescue Indoxyl Sulfate-Induced Deterioration of Osteoblastogenesis via the Aryl Hydrocarbon Receptor /MAPK PathwayWen-Chih Liu0Jia-Fwu Shyu1Yuh-Feng Lin2Hui-Wen Chiu3Paik Seong Lim4Chien-Lin Lu5Cai-Mei Zheng6Yi-Chou Hou7Po-Han Chen8Kuo-Cheng Lu9Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Biology and Anatomy, National Defense Medical Center, Taipei 114, TaiwanGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDivision of Nephrology, Department of Internal Medicine, Tungs’ Taichung MetroHarbor Hospital, Taichung City 435, TaiwanDivision of Nephrology, Department of Medicine, Fu Jen Catholic University Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 242, TaiwanGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanGraduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Biology and Anatomy, National Defense Medical Center, Taipei 114, TaiwanDivision of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 231, TaiwanIndoxyl 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.https://www.mdpi.com/1422-0067/21/20/7483aryl hydrocarbon receptorindoxyl sulfateosteoblastchronic kidney diseaseRunx2mitogen-activated protein kinase |
| spellingShingle | 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 Resveratrol Rescue Indoxyl Sulfate-Induced Deterioration of Osteoblastogenesis via the Aryl Hydrocarbon Receptor /MAPK Pathway International Journal of Molecular Sciences aryl hydrocarbon receptor indoxyl sulfate osteoblast chronic kidney disease Runx2 mitogen-activated protein kinase |
| title | Resveratrol Rescue Indoxyl Sulfate-Induced Deterioration of Osteoblastogenesis via the Aryl Hydrocarbon Receptor /MAPK Pathway |
| title_full | Resveratrol Rescue Indoxyl Sulfate-Induced Deterioration of Osteoblastogenesis via the Aryl Hydrocarbon Receptor /MAPK Pathway |
| title_fullStr | Resveratrol Rescue Indoxyl Sulfate-Induced Deterioration of Osteoblastogenesis via the Aryl Hydrocarbon Receptor /MAPK Pathway |
| title_full_unstemmed | Resveratrol Rescue Indoxyl Sulfate-Induced Deterioration of Osteoblastogenesis via the Aryl Hydrocarbon Receptor /MAPK Pathway |
| title_short | Resveratrol Rescue Indoxyl Sulfate-Induced Deterioration of Osteoblastogenesis via the Aryl Hydrocarbon Receptor /MAPK Pathway |
| title_sort | resveratrol rescue indoxyl sulfate induced deterioration of osteoblastogenesis via the aryl hydrocarbon receptor mapk pathway |
| topic | aryl hydrocarbon receptor indoxyl sulfate osteoblast chronic kidney disease Runx2 mitogen-activated protein kinase |
| url | https://www.mdpi.com/1422-0067/21/20/7483 |
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