Artesunate suppresses RANKL-induced osteoclastogenesis through inhibition of PLCγ1-Ca2+–NFATc1 signaling pathway and prevents ovariectomy-induced bone loss

Xiangzhou Zeng, Yueyang Zhang, Song Wang, Keng Wang, Lei Tao, Min Zou, Nana Chen, Jiake Xu, Shuwen Liu, Xiaojuan Li

    Research output: Contribution to journalArticle

    14 Citations (Scopus)

    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 12.5 μM. Artesunate obviously reduced RANKL-induced NF-κB-luc activity at 50 μM, 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 12.5 μM 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 μM. Further study revealed that artesunate inhibited RANKL up-regulated PLCγ1 activation, intracellular calcium, and calcineurin (PP2B-Aα) protein expression from 3.125 to 12.5 μM. 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.

    Original languageEnglish
    Pages (from-to)57-68
    Number of pages12
    JournalBiochemical Pharmacology
    Volume124
    DOIs
    Publication statusPublished - 15 Jan 2017

    Fingerprint

    Ovariectomy
    Osteogenesis
    Bone
    Bone and Bones
    Calcineurin
    Bone Diseases
    Chemical activation
    Osteoclasts
    Luciferases
    Rheumatoid Arthritis
    Cathepsin K
    artesunate
    Osteolysis
    Bone Resorption
    Nuclear Proteins
    Matrix Metalloproteinases
    Gene expression
    Malaria
    Osteoporosis
    Tumors

    Cite this

    Zeng, Xiangzhou ; Zhang, Yueyang ; Wang, Song ; Wang, Keng ; Tao, Lei ; Zou, Min ; Chen, Nana ; Xu, Jiake ; Liu, Shuwen ; Li, Xiaojuan. / Artesunate suppresses RANKL-induced osteoclastogenesis through inhibition of PLCγ1-Ca2+–NFATc1 signaling pathway and prevents ovariectomy-induced bone loss. In: Biochemical Pharmacology. 2017 ; Vol. 124. pp. 57-68.
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    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 12.5 μM. Artesunate obviously reduced RANKL-induced NF-κB-luc activity at 50 μM, 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 12.5 μM 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 μM. Further study revealed that artesunate inhibited RANKL up-regulated PLCγ1 activation, intracellular calcium, and calcineurin (PP2B-Aα) protein expression from 3.125 to 12.5 μM. 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.",
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    Artesunate suppresses RANKL-induced osteoclastogenesis through inhibition of PLCγ1-Ca2+–NFATc1 signaling pathway and prevents ovariectomy-induced bone loss. / Zeng, Xiangzhou; Zhang, Yueyang; Wang, Song; Wang, Keng; Tao, Lei; Zou, Min; Chen, Nana; Xu, Jiake; Liu, Shuwen; Li, Xiaojuan.

    In: Biochemical Pharmacology, Vol. 124, 15.01.2017, p. 57-68.

    Research output: Contribution to journalArticle

    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

    PY - 2017/1/15

    Y1 - 2017/1/15

    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 12.5 μM. Artesunate obviously reduced RANKL-induced NF-κB-luc activity at 50 μM, 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 12.5 μM 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 μM. Further study revealed that artesunate inhibited RANKL up-regulated PLCγ1 activation, intracellular calcium, and calcineurin (PP2B-Aα) protein expression from 3.125 to 12.5 μM. 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.

    AB - 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 μM. Artesunate obviously reduced RANKL-induced NF-κB-luc activity at 50 μM, 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 12.5 μM 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 μM. Further study revealed that artesunate inhibited RANKL up-regulated PLCγ1 activation, intracellular calcium, and calcineurin (PP2B-Aα) protein expression from 3.125 to 12.5 μM. 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.

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