Andrographolide suppresses RANKL-induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo
Andrographolide suppresses RANKL-induced osteoclastogenesis in vitro and prevents inflammatory bone loss in vivo
复制标题
穿心莲内酯在体外抑制 RANKL 诱导的破骨细胞生成，并在体内预防炎症性骨质流失
DOI：
10.1111/bph.12463
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发表时间：
2014-02-01
影响因子：
7.3
通讯作者：
Dai, K. R.
中科院分区：
文献类型：
--
作者：
Zhai, Z. J.;Li, H. W.;Dai, K. R.
背景和目的破骨细胞在骨质疏松、类风湿性关节炎和肿瘤骨转移等疾病中发挥着关键作用。因此，寻找可抑制破骨细胞形成和/或功能的天然化合物有望用于治疗破骨细胞相关疾病。在这里，我们研究了穿心莲内酯（AP）对破骨细胞生成和 LPS 诱导的骨溶解的变化，穿心莲内酯是从传统中国和印度药用植物穿心莲中分离出来的二萜内酯。实验方法在体外测量了 AP 对破骨细胞分化和骨吸收的影响。使用蛋白质印迹和 RT-PCR 技术来检查潜在的分子机制。在骨质溶解小鼠模型中评估了体内 AP 的骨保护活性。 主要结果 在体外，AP 浓度依赖性抑制 RANKL 介导的破骨细胞分化和骨吸收，并减少破骨细胞特异性标记物的表达，包括抗酒石酸酸性磷酸酶、降钙素受体和组织蛋白酶 K。进一步的分子分析表明，AP 损害了 RANKL 诱导的破骨细胞分化和骨吸收。 通过抑制 TGF 激活激酶 1 的磷酸化、抑制 IB 的磷酸化和降解，进而阻止 NF-B p65 亚基的核转位来实现 NF-B 信号转导。 AP 还抑制 ERK/MAPK 信号通路，而不影响 p38 或 JNK 信号通路。结论和意义 AP 在体外通过减弱 NF-B 和 ERK/MAPK 信号通路抑制 RANKL 诱导的破骨细胞生成，从而防止体内骨质流失。这些数据表明AP是一种有前途的天然化合物，用于治疗破骨细胞相关的骨疾病。
Background and PurposeOsteoclasts play a pivotal role in diseases such as osteoporosis, rheumatoid arthritis and tumour bone metastasis. Thus, searching for natural compounds that may suppress osteoclast formation and/or function is promising for the treatment of osteoclast-related diseases. Here, we examined changes in osteoclastogenesis and LPS-induced osteolysis in response to andrographolide (AP), a diterpenoid lactone isolated from the traditional Chinese and Indian medicinal plant Andrographis paniculata.Experimental ApproachEffects of AP on osteoclast differentiation and bone resorption were measured in vitro. Western blots and RT-PCR techniques were used to examine the underlying molecular mechanisms. The bone protective activity of APin vivo was assessed in a mouse model of osteolysis.Key ResultsAP concentration-dependently suppressed RANKL-mediated osteoclast differentiation and bone resorption in vitro and reduced the expression of osteoclast-specific markers, including tartrate-resistant acid phosphatase, calcitonin receptors and cathepsin K. Further molecular analysis revealed that AP impaired RANKL-induced NF-B signalling by inhibiting the phosphorylation of TGF--activated kinase 1, suppressing the phosphorylation and degradation of IB, and subsequently preventing the nuclear translocation of the NF-B p65 subunit. AP also inhibited the ERK/MAPK signalling pathway without affecting p38 or JNK signalling.Conclusions and ImplicationsAP suppressed RANKL-induced osteoclastogenesis through attenuating NF-B and ERK/MAPK signalling pathways in vitro, thus preventing bone loss in vivo. These data indicated that AP is a promising natural compound for the treatment of osteoclast-related bone diseases.