Anti-osteoclastogenic activity of isoliquiritigenin via inhibition of NF-κB-dependent autophagic pathway
Anti-osteoclastogenic activity of isoliquiritigenin via inhibition of NF-κB-dependent autophagic pathway
复制标题
异甘草素通过抑制 NF-κ B 依赖性自噬途径发挥抗破骨细胞活性
DOI：
10.1016/j.bcp.2016.03.002
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发表时间：
2016-04-15
影响因子：
5.8
通讯作者：
Peng, Bin
中科院分区：
文献类型：
--
作者：
Liu, Shan;Zhu, Lingxin;Peng, Bin
以往的研究，包括我们实验室的研究，已经证明了天然黄酮类化合物异甘草素（ISL）是一种有前途的骨质破坏性疾病的药物。然而，其抗破骨细胞生成作用的机制仍远不清楚。在此，我们评估了自噬和核因子-κ B（NF-κ B）在体外和体内抗破骨细胞生成作用过程中的潜在变化。我们观察到ISL抑制核因子-κ B配体受体激活剂（RANKL）诱导的破骨细胞生成，并抑制自噬微管相关蛋白轻链3（LC 3）-II和Beclin 1的积累。ISL处理导致破骨细胞前体中自噬的几个特定特征的中断，包括酸性囊泡细胞器形成、LC 3-II积累和自噬空泡的出现。在ISL处理的破骨细胞前体中，RANKL刺激的自噬相关基因和蛋白的表达水平也降低。雷帕霉素对自噬的再激活几乎逆转了ISL引起的抗破骨细胞生成作用。有趣的是，ISL抑制RANKL刺激的NF-κ B表达和核转位，而NF-κ B抑制剂Bay 11-7082显著抑制RANKL诱导的自噬激活。与体外结果一致，ISL的给药可减弱破骨细胞生成性组织蛋白酶K、自噬LC 3和NF-κ B表达，以防止体内炎性颅骨侵蚀。我们的研究结果强调了抑制NF-κ B依赖性自噬是ISL介导的抗破骨细胞生成活性的重要机制。(C)2016 Elsevier Inc. All rights reserved.
Previous studies, including those from our laboratory, have demonstrated that the natural flavonoid isoliquiritigenin (ISL) is a promising agent for bone destructive diseases. However, the mechanisms underlying its anti-osteoclastogenic effects are still far from clear. Here, we evaluated the potential alterations of autophagy and nuclear factor-kappa B (NF-kappa B) during anti-osteoclastogenic effects by ISL in vitro and in vivo. We observed that ISL inhibited the receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclastogenesis and suppressed autophagic microtubule-associated protein light chain 3 (LC3)-II and Beclin 1 accumulation. ISL treatment resulted in the interruption of several specific features for autophagy in osteoclast precursors, including acidic vesicular organelle formation, LC3-II accumulation, and appearance of autophagic vacuoles. The RANKL-stimulated expression levels of autophagy-related genes and proteins also diminished in ISL-treated osteoclast precursors. The reactivation of autophagy by rapamycin almost reversed the ISL-elicited anti-osteoclastogenic effects. Interestingly, ISL inhibited the RANKL-stimulated NF-kappa B expression and nuclear translocation, whereas the NF-kappa B inhibitor Bay 11-7082 markedly suppressed the RANKL-induced autophagic activation. Consistent with the in vitro results, the administration of ISL could attenuate osteoclastogenic cathepsin K, autophagic LC3, and NF-kappa B expression to protect against inflammatory calvarial bone erosion in vivo. Our findings highlight the inhibition of NF-kappa B-dependent autophagy as an important mechanism of ISL-mediated anti-osteoclastogenic activity. (C) 2016 Elsevier Inc. All rights reserved.