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ABD56 causes osteoclast apoptosis by inhibiting the NFkappaB and ERK pathways |
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| Authors: | Idris Aymen I Idris Aymen Mrak Emanuela Greig Iain Guidobono Francesca Ralston Stuart H van 't Hof Rob |
| Institution: | a Rheumatic Diseases Unit, Molecular Medicine Centre, University of Edinburgh, General Western Hospital, Edinburgh, EH4 2XU, UK b Bone Metabolic Unit, Scientific Institute H San Raffaele, via Olgettina 60, 20132 Milano, Italy c Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milano, via Vanvitelli 32, 20129 Milano, Italy d Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK |
| Abstract: | We have previously shown that the biphenylcarboxylic acid butanediol ester (ABD56) inhibits osteoclast formation and activity in vitro and in vivo. However, the mechanism of action of this compound is unknown. ABD56 inhibited osteoclast formation and caused osteoclast apoptosis, but had no effects on osteoblasts or macrophages. As the NFκB and MAPK pathways are essential for osteoclast formation and survival, we studied the effects of ABD56 on these pathways. ABD56 caused phosphorylation of p38, JNK and nuclear translocation of c-jun in osteoclasts. ABD56-induced apoptosis was prevented by the caspase inhibitor zVAD-fmk but was not prevented by the p38- or JNK-inhibitors. ABD56 completely abolished RANKL-induced IκB and ERK1/2 phosphorylation. Increasing the amount of RANKL partially rescued ABD56-induced apoptosis, indicating that the apoptosis is most probably due to the inhibition of survival signals such as ERK and NFκB, rather than activation of the p38 or Jnk MAPK pathways. |
| Keywords: | Osteoclast Apoptosis RANKL NFκB JNK ERK p38 |
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