Bortezomib inhibits human osteoclastogenesis

In multiple myeloma, the overexpression of receptor activator of nuclear factor kappa B ( NF- kappa B) ligand ( RANKL) leads to the induction of NF- kappa B 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- jB inhibition using bortezomib ( PS- 341) and I- kappa B 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 mitogenactivated protein kinase pathways, whereas the later phase of differentiation and activation occurred due to inhibition of p38, AP- 1 and NF- jB 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.