The Simultaneous Inhibitory Effect of Niclosamide on RANKL-Induced Osteoclast Formation and Osteoblast Differentiation.
The Simultaneous Inhibitory Effect of Niclosamide on RANKL-Induced Osteoclast Formation and Osteoblast Differentiation.
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DOI：
10.7150/ijms.19268
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发表时间：
2017
影响因子：
3.6
通讯作者：
Chang DM
中科院分区：
文献类型：
--
作者：
Liu FL;Chen CL;Lee CC;Wu CC;Hsu TH;Tsai CY;Huang HS;Chang DM
成骨细胞和破骨细胞的生成失衡导致骨质疏松、类风湿性关节炎等骨破坏性疾病。NF-κB通路的抑制是导致破骨细胞生成减少的原因。近年来研究表明，FDA批准的抗蠕虫药氯硝柳胺通过靶向NF-κB信号通路抑制前列腺癌和乳腺癌细胞生长。本研究探讨氯硝柳胺对体外培养的破骨细胞和成骨细胞分化及功能的影响。在RANKL诱导的小鼠破骨细胞前体细胞RAW 264.7和M-CSF/RANKL刺激的原代小鼠骨髓源性巨噬细胞（BMM）中，氯硝柳胺在0.5 μ M和1 μ M之间剂量依赖性地抑制TRAP阳性多核破骨细胞的形成和吸收陷窝的形成。此外，氯硝柳胺通过干扰TRAF-6、Erk 1/2、JNK和NF-κB活化途径，抑制M-CSF/RANKL刺激的BMM中活化T细胞核因子c1（NFATc 1）和破骨细胞分化相关基因的表达。然而，氯硝柳胺的细胞毒性作用在抑制破骨细胞生成的有效浓度（0.5- 1 μ M）下明显出现，在成骨细胞前体细胞系MC 3 T3-E1中通过caspase-3活化而增加凋亡。氯硝柳胺还可抑制MC 3 T3-E1的ALP活性、骨矿化和成骨细胞分化相关基因的表达。因此，我们的研究结果提出了一个新的观点，即氯硝柳胺对骨骼的影响必须考虑之前，将其应用于任何治疗。
The bone destruction disease including osteoporosis and rheumatoid arthritis are caused by the imbalance between osteoblastogenesis and osteoclastogenesis. Inhibition of the NF-κB pathway was responsible for decreased osteoclastogenesis. Recently many studies indicated that niclosamide, the FDA approved an antihelminth drug, inhibits prostate and breast cancer cells growth by targeting NF-κB signaling pathways. This study evaluated the effects of niclosamide on osteoclast and osteoblast differentiation and function in vitro. In RANKL-induced murine osteoclast precursor cell RAW264.7 and M-CSF/RANKL-stimulated primary murine bone marrow-derived macrophages (BMM), niclosamide dose-dependently inhibited the formation of TRAP-positive multinucleated osteoclasts and resorption pits formation between 0.5uM and 1uM. In addition, niclosamide suppressed the expression of nuclear factor of activated T cells c1 (NFATc1) and osteoclast differentiated-related genes in M-CSF/ RANKL-stimulated BMM by interference with TRAF-6, Erk1/2, JNK and NF-κB activation pathways. However, the cytotoxic effects of niclosamide obviously appeared at the effective concentrations for inhibiting osteoclastogenesis (0.5-1uM) with increase of apoptosis through caspase-3 activation in osteoblast precursor cell line, MC3T3-E1. Niclosamide also inhibited ALP activity, bone mineralization and osteoblast differentiation-related genes expression in MC3T3-E1. Therefore, our findings suggest the new standpoint that niclosamide's effects on bones must be considered before applying it in any therapeutic treatment.
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影响因子：
2.3
作者：
Karmakar, Sougata;Kay, Jonathan;Gravallese, Ellen M.
通讯作者：
Gravallese, Ellen M.
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影响因子：
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影响因子：
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作者：
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11.2
作者：
Jin, Yanli;Lu, Zhongzheng;Pan, Jingxuan
通讯作者：
Pan, Jingxuan
影响因子：
4.8
作者：
Galibert, L;Tometsko, ME;Dougall, WC
通讯作者：
Dougall, WC