Bortezomib inhibits human osteoclastogenesis.
In multiple myeloma, the overexpression of receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL) leads to the induction of NF-kappaB and activator protein-1 (AP-1)-related osteoclast activation and enhanced bone resorption. The purpose of this study was to examine the molecular and functional effects of proteasome inhibition in RANKL-induced osteoclastogenesis. Furthermore, we aimed to compare the outcome of proteasome versus selective NF-kappaB inhibition using bortezomib (PS-341) and I-kappaB kinase inhibitor PS-1145. Primary human osteoclasts were derived from CD14+ precursors in presence of RANKL and macrophage colony-stimulating factor (M-CSF). Both bortezomib and PS-1145 inhibited osteoclast differentiation in a dose- and time-dependent manner and furthermore, the bone resorption activity of osteoclasts. The mechanisms of action involved in early osteoclast differentiation were found to be related to the inhibition of p38 mitogen-activated protein kinase pathways, whereas the later phase of differentiation and activation occurred due to inhibition of p38, AP-1 and NF-kappaB activation. The AP-1 blockade contributed to significant reduction of osteoclastic vascular endothelial growth factor production. In conclusion, our data demonstrate that proteasomal inhibition should be considered as a novel therapeutic option of cancer-induced lytic bone disease.
von Metzler
I
I
Department of Hematology and Oncology, Charité - Universitätsmedizin Berlin, and Deutsches Rheumaforschungszentrum, Berlin, Germany.
Krebbel
H
H
Hecht
M
M
Manz
R A
RA
Fleissner
C
C
Mieth
M
M
Kaiser
M
M
Jakob
C
C
Sterz
J
J
Kleeberg
L
L
Heider
U
U
Sezer
O
O
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009101:Multiple Myeloma / Q000150:complications*; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; D006575:Heterocyclic Compounds, 3-Ring; D016328:NF-kappa B; C456319:PS1145; D011719:Pyrazines; D011725:Pyridines; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D018808:Transcription Factor AP-1; D042461:Vascular Endothelial Growth Factor A; D000069286:Bortezomib; D048051:p38 Mitogen-Activated Protein Kinases