Timosaponin AIII attenuates inflammatory injury in AGEs-induced osteoblast and alloxan-induced diabetic osteoporosis zebrafish by modulating the RAGE/MAPK signaling pathways
Timosaponin AIII attenuates inflammatory injury in AGEs-induced osteoblast and alloxan-induced diabetic osteoporosis zebrafish by modulating the RAGE/MAPK signaling pathways
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DOI：
10.1016/j.phymed.2020.153247
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发表时间：
2020-08-15
期刊：
影响因子：
7.9
通讯作者：
Shou, Dan
中科院分区：
文献类型：
--
作者：
Wang, Nani;Xu, Pingcui;Shou, Dan
背景：晚期糖基化终末产物（AGE）沉积会导致成骨细胞炎症损伤，并导致糖尿病性骨质疏松症。晚期糖基化终产物/丝裂原激活蛋白激酶通路(RAGE/MAPK)信号通路受体与糖尿病骨质疏松的发病机制密切相关。 Timosaponin AIII 是从知母（天门冬科）中分离得到的一种甾体皂苷，具有抗炎和抗骨质疏松作用。目的：本研究旨在探讨知母皂苷 AIII 对糖尿病骨质疏松症的治疗作用，以及其作用是否依赖于通过抑制 RAGE/MAPK 信号来保护成骨细胞免受 AGEs 诱导的损伤。方法：四氧嘧啶诱导的糖尿病骨质疏松症采用斑马鱼模型研究知莫皂苷AIII的体内作用，并以阿仑膦酸钠作为阳性对照。此外，还在原代大鼠成骨细胞中探索了相关机制。应用分子对接研究知莫皂苷 AIII 和 RAGE 之间的相互作用。结果：知母皂苷 AIII 处理逆转了四氧嘧啶引起的幼虫头部骨骼矿化面积的减少，同时降低了斑马鱼的甘油三酯和总胆固醇水平。此外，AGEs显着影响RAGE表达、碱性磷酸酶活性、白细胞介素15表达、白细胞介素6表达和肿瘤坏死因子-a表达，并增加细胞凋亡。 Timosaponin AIII 显着下调 AGE 诱导的白细胞介素 15、白细胞介素 6 和肿瘤坏死因子 -a 水平，并上调碱性磷酸酶和骨钙素水平。 Timosaponin AIII 还显着降低 RAGE 的表达，并对 AGE 诱导的成骨细胞中的下游 P38、细胞外信号调节激酶和 c-Jun N 末端激酶产生累加效应。分子对接预测知莫皂苷 AIII 和 RAGE 之间发生氢和疏水相互作用。结论：这些数据阐明知莫皂苷 AIII 通过抑制 RAGE/MAPK 信号通路的新机制减轻糖尿病骨质疏松症。我们的发现凸显了知莫皂苷 AIII 作为抗糖尿病骨质疏松症药物的潜在价值。
Background: Advanced glycation end products (AGEs) deposition causes inflammatory injury in osteoblasts and contributes to diabetic osteoporosis. The receptor for advanced glycation end product/mitogen-activated protein kinase pathway (RAGE/MAPK) signaling pathway is closely linked to the pathogenesis of diabetic osteoporosis. Timosaponin AIII, a steroidal saponin isolated from Anemarrhena asphodeloides Bunge (Asparagaceae), shows anti-inflammatory and anti-osteoporosis effects.Purpose: The present study was aimed to investigate the therapeutic effects of timosaponin AIII on diabetic osteoporosis and whether its effect is dependent on protecting osteoblasts against AGEs-induced injury via RAGE/MAPK signaling suppression.Methods: An alloxan-induced diabetic osteoporosis zebrafish model was applied to investigate the effects of timosaponin AIII in vivo, and alendronate was used as a positive control. Moreover, related mechanisms were explored in primary rat osteoblasts. Molecular docking was applied to investigate the interactions between timosaponin AIII and RAGE.Results: Timosaponin AIII treatment reversed alloxan-induced reduction in the mineralized area of the larvae head skeleton, accompanied by a decreased level of triglyceride and total cholesterol in the zebrafish. Additionally, AGEs significantly influenced RAGE expression, alkaline phosphatase activity, interleukin 15 expression, interleukin 6 expression, and tumor necrosis factor-a expression, and increased cell apoptosis. Timosaponin AIII significantly downregulated AGEs-induced interleukin 15, interleukin 6, and tumor necrosis factor-a levels, and upregulated alkaline phosphatase and osteocalcin levels. Timosaponin AIII also significantly reduced the expression of RAGE and had additive effects on downstream P38, extracellular signal-regulated kinase and c-Jun N-terminal kinase in AGEs-induced osteoblast. Molecular docking predicted that hydrogen and hydrophobic interactions occurred between timosaponin AIII and RAGE.Conclusion: These data clarified that timosaponin AIII attenuates diabetic osteoporosis via a novel mechanism involved suppressing the RAGE/MAPK signaling pathway. Our finding highlights the potential value of timosaponin AIII as an anti-diabetic osteoporosis agent.