ABD56 causes osteoclast apoptosis by inhibiting the NFkappaB and ERK pathways.
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 NFkappaB 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 IkappaB 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 NFkappaB, rather than activation of the p38 or Jnk MAPK pathways.
Idris
Aymen I
AI
Rheumatic Diseases Unit, Molecular Medicine Centre, University of Edinburgh, General Western Hospital, Edinburgh, EH4 2XU, UK.
Idris
Aymen
A
Mrak
Emanuela
E
Greig
Iain
I
Guidobono
Francesca
F
Ralston
Stuart H
SH
van 't Hof
Rob
R
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects
D000590:Amino Acid Chloromethyl Ketones; D001565:Benzoates; D001713:Biphenyl Compounds; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D016328:NF-kappa B; D053245:RANK Ligand; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C529241:biphenylcarboxylic acid butanediol ester; D048049:Extracellular Signal-Regulated MAP Kinases