Small molecule inhibitors of IkappaB kinase signaling inhibit osteoclast formation in vitro and prevent ovariectomy-induced bone loss in vivo.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Aymen I IdrisStuart H Ralston

Abstract

The NFκB pathway plays a critical role in the regulation of osteoclast activity, and activation of the pathway is dependent on IκB kinase (IKK), which phosphorylates IκB, targeting it for proteasomal degradation. Pharmacological inhibitors of IKK exhibit anti-inflammatory properties and prevent bone erosions in models of inflammatory arthritis. However, the effects of these agents on osteoblast function and ovariectomy-induced bone loss remain unknown. Here we examined the effects of the IKK inhibitors celastrol, BMS-345541, and parthenolide on bone cell function in vitro and ovariectomy-induced bone loss in vivo. All three compounds inhibited RANKL-induced signaling in osteoclasts, caused osteoclast apoptosis, and inhibited osteoclast formation. Although parthenolide and BMS-345541 had no inhibitory effects on osteoblast function, celastrol prevented IL1β-induced TAK1 activation and inhibited osteoblast growth, differentiation, and bone nodule formation. The selective IKK inhibitors parthenolide and BMS-345541 prevented ovariectomy-induced bone loss by inhibiting osteoclastic bone resorption. We conclude that pharmacological inhibitors of IKK inhibit several critical signaling pathways in osteoclasts necessary for cell surviva...Continue Reading

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Citations

May 29, 2013·Biomaterials·Masahiro YamadaTakahiro Ogawa
May 3, 2012·The Journal of Biological Chemistry·Siddaraju M NanjundaiahKamal D Moudgil
Jan 11, 2013·Mediators of Inflammation·Tao YuJae Youl Cho
Jul 14, 2016·Pathogens and Disease·Shivaprasad H VenkateshaKamal D Moudgil
Feb 20, 2018·Calcified Tissue International·Silvia MarinoAymen I Idris
Dec 15, 2015·PloS One·Rita CascãoJoão E Fonseca
May 4, 2018·Scientific Reports·Daniëlle de RidderAymen I Idris
Jul 22, 2014·Molecular Nutrition & Food Research·Robin J SoperStephen J Hodges
Jul 25, 2015·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Ali KassemUlf H Lerner
Apr 18, 2018·Oncotarget·Silvia MarinoAymen I Idris
Jul 1, 2017·Frontiers in Medicine·Rita CascãoLuis F Moita
Jul 22, 2015·The Journal of Biological Chemistry·Antonia SophocleousAymen I Idris
Oct 6, 2020·Frontiers in Medicine·Rita CascãoJoão Eurico Fonseca

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