山药酸通过靶向 RANKL 诱导的细胞内信号通路减弱破骨细胞生成和骨吸收,Journal of Cellular Physiology

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山药酸通过靶向 RANKL 诱导的细胞内信号通路减弱破骨细胞生成和骨吸收
Journal of Cellular Physiology ( IF 4.5 ) Pub Date : 2021-11-19 , DOI: 10.1002/jcp.30642
Gang Wang _{1,

2,

3} , Kai Chen ₂ , Chao Ma ₃ , Chao Wang ₂ , Delong Chen _{2,

4} , Jianbo He _{2,

5} , Yuhao Liu _{1,

2} , Tao Jiang ₆ , Jinbo Yuan ₂ , Leilei Chen ₇ , Wei He ₇ , Jiake Xu ₂

Affiliation

破骨细胞的过度活动会导致骨骼疾病，例如骨质疏松症和骨质溶解。然而，目前针对破骨细胞的药物存在各种缺陷，将天然化合物作为具有巨大潜力的替代品。Roburic acid (RA) 是从龙胆草中提取的一种三萜类化合物，对炎症和氧化具有抑制作用。本研究采用体外破骨细胞生成模型，研究 RA 对核因子-κB 配体 (RANKL) 受体激活剂诱导的细胞内信号传导的影响和机制。正如预期的那样，浓度范围为 1 至 10 μM 的 RA 抑制了骨髓巨噬细胞 (BMM) 的破骨细胞分化，但没有细胞毒性。有趣的是，RA 在体外对成骨细胞生成没有影响。此外，RA 减轻了 F-肌动蛋白环的形成，羟基磷灰石再吸收和破骨细胞中的基因表达。从机制上讲，RA 抑制了 TNF 受体相关因子 6 (TRAF6)，这是 RANKL-RANK 结合后的关键衔接蛋白。一方面，RA 下调核因子-κB (NF-κB) 活性、细胞外调节蛋白激酶 (ERK) 磷酸化和钙振荡。另一方面，RA 上调抗氧化反应元件 (ARE) 反应和血红素加氧酶 (HO)-1 的蛋白表达。这些上游改变最终导致激活 T 细胞核因子 1 (NFATc1) 活性的抑制和参与破骨细胞生成和骨吸收的蛋白质的表达。此外，通过使用去卵巢 (OVX) 小鼠模型，发现 RA 对骨质流失具有治疗作用。鉴于这些发现，

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Roburic acid attenuates osteoclastogenesis and bone resorption by targeting RANKL-induced intracellular signaling pathways

Excessive activity of osteoclasts contributes to skeletal diseases such as osteoporosis and osteolysis. However, current drugs targeting osteoclast have various deficiencies, placing natural compounds as substitutions of great potential. Roburic acid (RA) is a triterpenoid exacted from Radix Gentianae Macrophyllae, which exhibits inhibitory effects on inflammation and oxidation. By employing an in vitro osteoclastogenesis model, this study investigates the effects and mechanisms of RA on intracellular signaling induced by receptor activator of nuclear factor-κB ligand (RANKL). As expected, RA at a concentration scope from 1 to 10 μM dampened the osteoclast differentiation of bone marrow macrophages (BMMs) but without cell toxicity. Interestingly, RA showed no effect on osteoblastogenesis in vitro. Furthermore, RA mitigated F-actin ring formation, hydroxyapatite resorption, and gene expression in osteoclasts. Mechanistically, RA suppressed TNF receptor-associated factor 6 (TRAF6), the crucial adaptor protein following RANKL-RANK binding. On the one hand, RA downregulated the nuclear factor-κB (NF-κB) activity, extracellular regulated protein kinases (ERK) phosphorylation, and calcium oscillations. On the other hand, RA upregulated the antioxidative response element (ARE) response and the protein expression of heme oxygenase (HO)-1. These upstream alterations eventually led to the suppression of the nuclear factor of activated T cells 1 (NFATc1) activity and the expression of proteins involved in osteoclastogenesis and bone resorption. Furthermore, by using an ovariectomized (OVX) mice model, RA was found to have therapeutic effects against bone loss. On account of these findings, RA could be used to restrain osteoclasts for treating osteoporosis and other osteolytic diseases.

更新日期：2021-11-19

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