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Artesunate suppresses RANKL-induced osteoclastogenesis through inhibition of PLCγ1-Ca2+-NFATc1 signaling pathway and prevents ovariectomy-induced bone loss.
Biochem Pharmacol. 2017 Jan 15; 124:57-68.BP

Abstract

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 12.5μM. Artesunate obviously reduced RANKL-induced NF-κB-luc activity at 50μM, but had no effects on RANKL-induced NF-κB activation (NF-κB luciferase activity, IκB-α degradation and nuclear NF-κB p65 protein level) from 3.125 to 12.5μM 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 12.5μM. Further study revealed that artesunate inhibited RANKL up-regulated PLCγ1 activation, intracellular calcium, and calcineurin (PP2B-Aα) protein expression from 3.125 to 12.5μM. 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 PLCγ1-Ca2+-calcineurin-NFATc1 pathway. Collectively, our data suggest that artesunate is a potential treatment option against RANKL-mediated osteolytic bone disease.

Authors+Show Affiliations

Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China; Department of Pharmacology, Hainan Medical College, Haikou 571199, China.Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.Department of Surgery, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou 510120, China.Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Australia.Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: liusw@smu.edu.cn.Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address: lixiaoj@smu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27789216

Citation

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, vol. 124, 2017, pp. 57-68.
Zeng X, Zhang Y, Wang S, et al. Artesunate suppresses RANKL-induced osteoclastogenesis through inhibition of PLCγ1-Ca2+-NFATc1 signaling pathway and prevents ovariectomy-induced bone loss. Biochem Pharmacol. 2017;124:57-68.
Zeng, X., Zhang, Y., Wang, S., Wang, K., Tao, L., Zou, M., Chen, N., Xu, J., Liu, S., & Li, X. (2017). Artesunate suppresses RANKL-induced osteoclastogenesis through inhibition of PLCγ1-Ca2+-NFATc1 signaling pathway and prevents ovariectomy-induced bone loss. Biochemical Pharmacology, 124, 57-68. https://doi.org/10.1016/j.bcp.2016.10.007
Zeng X, et al. Artesunate Suppresses RANKL-induced Osteoclastogenesis Through Inhibition of PLCγ1-Ca2+-NFATc1 Signaling Pathway and Prevents Ovariectomy-induced Bone Loss. Biochem Pharmacol. 2017 Jan 15;124:57-68. PubMed PMID: 27789216.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Artesunate suppresses RANKL-induced osteoclastogenesis through inhibition of PLCγ1-Ca2+-NFATc1 signaling pathway and prevents ovariectomy-induced bone loss. AU - Zeng,Xiangzhou, AU - Zhang,Yueyang, AU - Wang,Song, AU - Wang,Keng, AU - Tao,Lei, AU - Zou,Min, AU - Chen,Nana, AU - Xu,Jiake, AU - Liu,Shuwen, AU - Li,Xiaojuan, Y1 - 2016/10/24/ PY - 2016/08/02/received PY - 2016/10/21/accepted PY - 2016/10/30/pubmed PY - 2017/5/11/medline PY - 2016/11/6/entrez KW - Artesunate KW - Artesunate (PubChem CID: 16394563) KW - BAY11-7082 (PubChem CID: 5353431) KW - Cyclosporin A (CsA) (PubChem CID: 5284373) KW - NF-ATc1 KW - NF-κB KW - Osteoclast KW - RANKL KW - Zoledronic acid (PubChem CID: 68740) SP - 57 EP - 68 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 124 N2 - 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 12.5μM. Artesunate obviously reduced RANKL-induced NF-κB-luc activity at 50μM, but had no effects on RANKL-induced NF-κB activation (NF-κB luciferase activity, IκB-α degradation and nuclear NF-κB p65 protein level) from 3.125 to 12.5μM 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 12.5μM. Further study revealed that artesunate inhibited RANKL up-regulated PLCγ1 activation, intracellular calcium, and calcineurin (PP2B-Aα) protein expression from 3.125 to 12.5μM. 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 PLCγ1-Ca2+-calcineurin-NFATc1 pathway. Collectively, our data suggest that artesunate is a potential treatment option against RANKL-mediated osteolytic bone disease. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/27789216/Artesunate_suppresses_RANKL_induced_osteoclastogenesis_through_inhibition_of_PLCγ1_Ca2+_NFATc1_signaling_pathway_and_prevents_ovariectomy_induced_bone_loss_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(16)30376-8 DB - PRIME DP - Unbound Medicine ER -