Artesunate suppresses RANKL-induced osteoclastogenesis through inhibition of PLCγ1-Ca2+-NFATc1 signaling pathway and prevents ovariectomy-induced bone loss
机构：[1]Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China[2]Department of Pharmacology, Hainan Medical College, Haikou 571199, China[3]Department of Surgery, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou 510120, China广东省中医院[4]School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Australia
Bone lytic diseases including osteoporosis, rheumatoid arthritis, and bone metastatic tumors affect hundreds of millions people worldwide. Targeting over-activated osteoclasts as an anti-resorptive treatment becomes an important strategy to treat osteolytic diseases. Artesunate is a compound derived from artemisinin (qinghaosu) and has been used to treat malaria and rheumatoid arthritis clinically in China, but its role in osteolysis is unknown. Here, we found that artesunate could suppress RANKL-induced osteoclastogenesis and bone resorption from 1.56 to 12.5 mu M. Artesunate obviously reduced RANKL-induced NF-kappa B-luc activity at 50 mu M, but had no effects on RANKL-induced NF-kappa B activation (NF-kappa B luciferase activity, IKB-alpha degradation and nuclear NF-kappa B p65 protein level) from 3.125 to 12.5 mu M in pre-osteoclastic RAW264.7 cells. Interestingly, artesunate could significantly inhibit RANKL-induced NFATc1 activation measured by NFAT luciferase activity, NFATc1 mRNA and nuclear NFATc1 protein levels from 3.125 to 12.5 mu M. Further study revealed that artesunate inhibited RANKL up-regulated PLC gamma 1 activation, intracellular calcium, and calcineurin (PP2B-A alpha) protein expression from 3.125 to 12.5 mu M. In addition, the NFATc1 targeted osteoclast-specific genes expression including cathepsin K, MMP-9, and TRAP was reduced by artesunate. Finally, we showed that artesunate was able to reverse the bone loss in an ovariectomized mouse model in vivo accompanied with reduced RANKL, RANKL/OPG, and TRAP-5b levels. This study indicates that artesunate inhibits RANKL-induced osteoclastogenesis and bone loss by inhibiting PLC gamma 1-Ca2+-calcineurin-NFATc1 pathway. Collectively, our data suggest that artesunate is a potential treatment option against RANKL-mediated osteolytic bone disease. (C) 2016 Elsevier Inc. All rights reserved.
基金：
National Natural Science Foundation of Guangdong Province [2015A030313287]; National Natural Science Foundation of China [81373123, 81073119]; Guangdong Innovative and Entepreneurial Research Team Program [201001Y04675344]
第一作者机构：[1]Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China[2]Department of Pharmacology, Hainan Medical College, Haikou 571199, China
通讯作者：
通讯机构：[1]Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China[*1]Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, China
推荐引用方式(GB/T 7714)：
Zeng Xiangzhou,Zhang Yueyang,Wang Song,et al.Artesunate suppresses RANKL-induced osteoclastogenesis through inhibition of PLCγ1-Ca2+-NFATc1 signaling pathway and prevents ovariectomy-induced bone loss[J].BIOCHEMICAL PHARMACOLOGY.2017,124:57-68.doi:10.1016/j.bcp.2016.10.007.
APA：
Zeng, Xiangzhou,Zhang, Yueyang,Wang, Song,Wang, Keng,Tao, Lei...&Li, Xiaojuan.(2017).Artesunate suppresses RANKL-induced osteoclastogenesis through inhibition of PLCγ1-Ca2+-NFATc1 signaling pathway and prevents ovariectomy-induced bone loss.BIOCHEMICAL PHARMACOLOGY,124,
MLA：
Zeng, Xiangzhou,et al."Artesunate suppresses RANKL-induced osteoclastogenesis through inhibition of PLCγ1-Ca2+-NFATc1 signaling pathway and prevents ovariectomy-induced bone loss".BIOCHEMICAL PHARMACOLOGY 124.(2017):57-68
医学