Please use this identifier to cite or link to this item: https://doi.org/10.1002/jbmr.3031
Title: TRAF6 Mediates Suppression of Osteoclastogenesis and Prevention of Ovariectomy-Induced Bone Loss by a Novel Prenylflavonoid
Authors: Tan, Ee Min 
Li, Lei
Indran, Inthrani Raja 
Chew, Nicholas
Yong, Eu-Leong 
Keywords: Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
OSTEOCLASTS
CELL
TISSUE SIGNALINGTRANSCRIPTION FACTORS
OSTEOPOROSIS
ANIMAL MODELS
THERAPEUTICS
NF-KAPPA-B
VERTEBRAL FRACTURES
RECEPTOR ACTIVATOR
SIGNALING COMPLEX
IN-VITRO
RANKL
DIFFERENTIATION
ICARITIN
EXPRESSION
RAW264.7
Issue Date: 1-Apr-2017
Publisher: WILEY
Citation: Tan, 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
Abstract: Given 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.
Source Title: JOURNAL OF BONE AND MINERAL RESEARCH
URI: https://scholarbank.nus.edu.sg/handle/10635/205957
ISSN: 08840431
15234681
DOI: 10.1002/jbmr.3031
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