Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
Division of Nephrology, Department of Internal Medicine, Taipei Hospital, Ministry of Health and Welfare, New Taipei City 242, Taiwan.
Int J Mol Sci. 2020 Oct 11;21(20):7483. 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.
硫酸吲哚酚（IS）是一种源自肠道微生物代谢膳食色氨酸的尿毒症毒素，它是一种内源性芳烃受体（AhR）激动剂，也是骨重塑的关键参与者。白藜芦醇（RSV）是 AhR 拮抗剂，在保护 AhR 配体方面发挥着保护作用。我们的研究探讨了 IS 对成骨细胞分化的影响，并通过深入研究 AhR 信号通路，研究了 IS 控制成骨细胞生成标志物表达的可能机制。在体内，我们发现暴露于 IS 的 5/6 肾切除术的年轻成年 IS 小鼠的股骨组织学结构遭到破坏，包括 Runx2 抗原表达减少。RSV 改善了骨干结构、Runx2 表达和小梁质量。体外数据表明，IS 在 500 和 1000μM 时通过抑制 ERK 和 p38 丝裂原活化蛋白激酶（MAPK）通路干扰成骨细胞发生，而这两条通路被发现是 AhR 的下游通路。RSV 通过抑制 AhR 和下游信号转导，证明可以改善 IS 的抗成骨细胞生成作用。综上所述，我们证明了 IS/AhR/MAPK 信号通路在抑制成骨细胞发生中起着关键作用，RSV 具有逆转 IS 诱导的成骨细胞发育下降和抑制慢性肾脏病患者异常骨转换的潜在治疗作用。
