Artesunate attenuates LPS-induced osteoclastogenesis by suppressing TLR4/TRAF6 and PLCγ1-Ca^(2+)-NFATc1 signaling pathway  

作　　者：Xiang-zhou Zeng Yue-yang Zhang Qin Yang Song Wang Bin-hua Zou Yan-hui Tan Min Zou Shu-wen Liu Xiao-juan Li 

机构地区：[1]Laboratory of Anti-inflammatory and Immunomodulatory Pharmacology,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515,China [2]Guangdong Provincial Key Laboratory of New Drug Screening,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515,China [3]Department of Pharmacology,Hainan Medical College,Haikou 571199,China [4]Department of Surgery,Guangdong Hospital of Traditional Chinese Medicine,Guangzhou 510120,China

出　　处：《Acta Pharmacologica Sinica》2020年第2期229-236,共8页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(81773740,81073119,and 81611130078);the Natural Science Foundation of Guangdong Province,China(2015A030313287);the Natural Science Foundation of Hainan Province,China(817129).

摘　　要：In chronic infectious diseases caused by gram-negative bacteria,such as osteomyelitis,septic arthritis,and periodontitis,osteoclastic activity is enhanced with elevated inflammation,which disturbs the bone homeostasis and results in osteolysis.Lipopolysaccharide(LPS),as a bacteria product,plays an important role in this process.Recent evidence shows that an antimalarial drug artesunate attenuates LPS-induced osteolysis independent of RANKL.In this study we evaluated the effects of artesunate on LPS-induced osteoclastogenesis in vitro and femur osteolysis in vivo,and explored the mechanisms underlying the effects of artesunate on LPS-induced osteoclast differentiation independent of RANKL.In preosteoclastic RAW264.7 cells,we found that artesunate(1.56?12.5μM)dose dependently inhibited LPS-induced osteoclast formation accompanied by suppressing LPS-stimulated osteoclast-related gene expression(Fra-2,TRAP,Cathepsin K,β3-integrin,DC-STAMP,and Atp6v0d2).We showed that artesunate(3.125?12.5μM)inhibited LPS-stimulated nuclear factor of activated T cells c1(NFATc1)but not NF-κB transcriptional activity;artesunate(6.25,12.5μM)significantly inhibited LPS-stimulated NFATc1 protein expression.Furthermore,artesunate treatment markedly suppressed LPS-induced Ca2+influx,and decreased the expression of PP2B-Aα(calcineurin)and pPLCγ1 in the cells.In addition,artesunate treatment significantly decreased the expression of upstream signals TLR4 and TRAF6 during LPS-induced osteoclastogenesis.Administration of artesunate(10 mg/kg,ip)for 8 days effectively inhibited serum TNF-αlevels and ameliorated LPS(5 mg/kg,ip)-induced inflammatory bone loss in vivo.Taken together,artesunate attenuates LPS-induced inflammatory osteoclastogenesis by inhibiting the expression of TLR4/TRAF6 and the downstream PLCγ1-Ca^2+-NFATc1 signaling pathway.Artesunate is a valuable choice to treat bone loss induced by gram-negative bacteria infection or inflammation in RANKL-independent pathway.

关 键 词：ARTESUNATE OSTEOCLAST LPS PP2B-Aα CA^(2+) NFATc1 TLR4 RAW264.7 cells chronic INFECTIOUS diseases 

分 类 号：R965[医药卫生—药理学]