Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/136050
Title: MECHANISM OF A NATURAL PRENYLFLAVONOID, ICARITIN, AS AN ANTI-OSTEOCLAST AGENT FOR POSTMENOPAUSAL OSTEOPOROSIS: CELLULAR AND ANIMAL STUDIES
Authors: TAN EE MIN
Keywords: osteoclast, osteoporosis, ovariectomy, flavonoid, RANKL signaling, TRAF6
Issue Date: 9-Jan-2017
Source: TAN EE MIN (2017-01-09). MECHANISM OF A NATURAL PRENYLFLAVONOID, ICARITIN, AS AN ANTI-OSTEOCLAST AGENT FOR POSTMENOPAUSAL OSTEOPOROSIS: CELLULAR AND ANIMAL STUDIES. ScholarBank@NUS Repository.
Abstract: Given the limitations of current therapeutic options for postmenopausal osteoporosis, there is a need for alternatives with minimal adverse effects. In this thesis, 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 NFκB and MAPK/AP-1 pathways, thereby suppressing 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 NFκB, 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.
URI: http://scholarbank.nus.edu.sg/handle/10635/136050
Appears in Collections:Ph.D Theses (Open)

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
TanEM.pdf6.23 MBAdobe PDF

OPEN

NoneView/Download

Page view(s)

26
checked on Jan 20, 2018

Download(s)

24
checked on Jan 20, 2018

Google ScholarTM

Check


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.