Bortezomib inhibits human osteoclastogenesis.

Abstract

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.

• Authors: 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
• Journal: Leukemia (Leukemia) Vol. 21 Issue 9 Pg. 2025-34 (Sep 2007) ISSN: 0887-6924 [Print] England
• PMID: 17581612 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Boronic Acids
• Heterocyclic Compounds, 3-Ring
• NF-kappa B
• PS1145
• Pyrazines
• Pyridines
• RANK Ligand
• TNFSF11 protein, human
• Transcription Factor AP-1
• Vascular Endothelial Growth Factor A
• Bortezomib
• p38 Mitogen-Activated Protein Kinases

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Bone Resorption (drug therapy, etiology, pathology)
• Boronic Acids (pharmacology)
• Bortezomib
• Cell Differentiation (drug effects)
• Cell Lineage (drug effects)
• Female
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Humans
• In Vitro Techniques
• Male
• Multiple Myeloma (complications)
• NF-kappa B (metabolism)
• Osteoclasts (cytology, drug effects, metabolism)
• Pyrazines (pharmacology)
• Pyridines (pharmacology)
• RANK Ligand (metabolism)
• Signal Transduction (drug effects)
• Stem Cells (cytology, drug effects)
• Transcription Factor AP-1 (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)