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Myeloma

Bortezomib inhibits human osteoclastogenesis

Leukemia volume 21, pages 2025–2034 (2007)Cite this article

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.

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Acknowledgements

We thank H Kemmer for her excellent technical assistance. Grant support was provided by Deutsche Forschungsgemeinschaft (Klinische Forschergruppe KFO 105).

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  1. I von Metzler and H Krebbel: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Hematology and Oncology, Charité – Universitätsmedizin Berlin, and Deutsches Rheumaforschungszentrum, Berlin, Germany

    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

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Correspondence to O Sezer.

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von Metzler, I., Krebbel, H., Hecht, M. et al. Bortezomib inhibits human osteoclastogenesis. Leukemia 21, 2025–2034 (2007). https://doi.org/10.1038/sj.leu.2404806

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