Please use this identifier to cite or link to this item: https://doi.org/10.1002/jbmr.3031
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dc.titleTRAF6 Mediates Suppression of Osteoclastogenesis and Prevention of Ovariectomy-Induced Bone Loss by a Novel Prenylflavonoid
dc.contributor.authorTan, Ee Min
dc.contributor.authorLi, Lei
dc.contributor.authorIndran, Inthrani Raja
dc.contributor.authorChew, Nicholas
dc.contributor.authorYong, Eu-Leong
dc.date.accessioned2021-11-11T09:15:42Z
dc.date.available2021-11-11T09:15:42Z
dc.date.issued2017-04-01
dc.identifier.citationTan, Ee Min, Li, Lei, Indran, Inthrani Raja, Chew, Nicholas, Yong, Eu-Leong (2017-04-01). TRAF6 Mediates Suppression of Osteoclastogenesis and Prevention of Ovariectomy-Induced Bone Loss by a Novel Prenylflavonoid. JOURNAL OF BONE AND MINERAL RESEARCH 32 (4) : 846-860. ScholarBank@NUS Repository. https://doi.org/10.1002/jbmr.3031
dc.identifier.issn08840431
dc.identifier.issn15234681
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/205957
dc.description.abstractGiven the limitations of current therapeutic options for postmenopausal osteoporosis, there is a need for alternatives with minimal adverse effects. In this study, we evaluated the effects of icaritin (ICT), a natural prenylflavonoid, on osteoclastogenesis both in vitro and in an ovariectomized (OVX) rat model and investigated its underlying molecular mechanism(s) of action. ICT inhibited osteoclast formation in two osteoclast precursor models, RAW 264.7 mouse monocyte cell line and human PBMC. ICT also inhibited sealing zone and resorption pit formation in a dose-dependent manner. Mechanistically, ICT inhibited RANKL-induced NF-κB and MAPK/AP-1 pathways to suppress gene expression of nuclear factor of activated T cells (NFAT)c1, the master transcription regulator of osteoclast differentiation. ICT, by inhibiting the TRAF6/c-Src/PI3K pathway, suppressed NADPH oxidase-1 activation to attenuate intracellular ROS production and downregulate calcineurin phosphatase activity. As a result, NFATc1 nuclear translocation and activity was suppressed. Crucially, ICT promoted proteasomal degradation of TRAF6, the critical adaptor protein that transduces RANKL/RANK signaling, and the inhibitory effect of ICT on osteoclastogenesis was reversed by the proteasomal inhibitor MG 132. ICT administration inhibited OVX-induced bone loss and resorption by suppressing osteoclast formation and activity. Consistent with cellular studies, ICT downregulated TRAF6 and NFATc1 protein expression in CD11b+/Gr-1-/low osteoclast precursors isolated from OVX rats. Put together, we present novel findings that ICT, by downregulating TRAF6, coordinates inhibition of NF-κB, MAPK/AP-1, and ROS signaling pathways to reduce expression and activity of NFATc1. These results demonstrate the potential of ICT for treatment of postmenopausal osteoporosis and point to TRAF6 as a promising target for novel anti-osteoporotic drugs. © 2017 American Society for Bone and Mineral Research.
dc.language.isoen
dc.publisherWILEY
dc.sourceElements
dc.subjectScience & Technology
dc.subjectLife Sciences & Biomedicine
dc.subjectEndocrinology & Metabolism
dc.subjectOSTEOCLASTS
dc.subjectCELL
dc.subjectTISSUE SIGNALINGTRANSCRIPTION FACTORS
dc.subjectOSTEOPOROSIS
dc.subjectANIMAL MODELS
dc.subjectTHERAPEUTICS
dc.subjectNF-KAPPA-B
dc.subjectVERTEBRAL FRACTURES
dc.subjectRECEPTOR ACTIVATOR
dc.subjectSIGNALING COMPLEX
dc.subjectIN-VITRO
dc.subjectRANKL
dc.subjectDIFFERENTIATION
dc.subjectICARITIN
dc.subjectEXPRESSION
dc.subjectRAW264.7
dc.typeArticle
dc.date.updated2021-11-10T02:22:19Z
dc.contributor.departmentDEPT OF OBSTETRICS & GYNAECOLOGY
dc.contributor.departmentDEPT OF PHARMACOLOGY
dc.description.doi10.1002/jbmr.3031
dc.description.sourcetitleJOURNAL OF BONE AND MINERAL RESEARCH
dc.description.volume32
dc.description.issue4
dc.description.page846-860
dc.description.placeUnited States
dc.published.statePublished
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