Bortezomib inhibits human osteoclastogenesis

I. von Metzler, H. Krebbel, M. Hecht, R. A. Manz, C. Fleissner, M. Mieth, M. Kaiser, C. Jakob, J. Sterz, L. Kleeberg, U. Heider, O. Sezer*

*Korrespondierende/r Autor/-in für diese Arbeit
159 Zitate (Scopus)

Abstract

In multiple myeloma, the overexpression of receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) leads to the induction of NF-κB 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-κB inhibition using bortezomib (PS-341) and I-κB 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-κB 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.

OriginalspracheEnglisch
ZeitschriftLeukemia
Jahrgang21
Ausgabenummer9
Seiten (von - bis)2025-2034
Seitenumfang10
ISSN0887-6924
DOIs
PublikationsstatusVeröffentlicht - 09.2007

Strategische Forschungsbereiche und Zentren

  • Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

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