期刊
BIOCHEMICAL PHARMACOLOGY
卷 86, 期 12, 页码 1775-1783出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2013.09.017
关键词
SC-514; Bone marrow cells; Osteoclastogenesis; RANKL; NF-kappa B
资金
- National Health and Medical Research Council of Australia
- National Natural Science Foundation of China (NSFC) [81228013]
- University of Western Australia (UWA) Research Collaboration Awards
- Australia Endeavour Research Fellow
- Guangxi Medical University
The RANKL-induced NF-kappa B signaling pathway is essential for osteoclastogenesis. This study aims to identify specific inhibitors targeting NF-kappa B signaling pathway, which might serve as useful small molecule inhibitors for the treatment and alleviation of osteoclast-mediated bone lytic diseases. By screening for compounds that selectively inhibit RANKL-induced NF-kappa B activation in RAW264.7 cells as monitored by luciferase reporter gene assay, we identified SC-514, a specific inhibitor of IKK beta, as a candidate compound targeting osteoclastogenesis. SC-514 dose-dependently inhibits RANKL-induced osteoclastogenesis with an IC50 of <5 mu M. At high concentrations, SC-514 (>= 12.5 mu M) induced apoptosis and caspase 3 activation in RAW264.7 cells. Moreover, SC-514 specifically suppressed NF-kappa B activity owing to delayed RANKL-induced degradation of I kappa B alpha and inhibition of p65 nuclear translocation. Taken together, our results indicate that SC-514 impairs RANKL-induced osteoclastogenesis and NF-kappa B activation. Thus, targeting IKK beta by SC-514 presents as a potential treatment for osteoclast-related disorders such as osteoporosis and cancer-induced bone loss. (C) 2013 Elsevier Inc. All rights reserved.
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