Bortezomib inhibits maturation and function of osteoclasts from PBMCs of patients with multiple myeloma by downregulating TRAF6

Multiple myeloma (MM) is associated with increased activation of osteoclasts, causing enhanced bone degradation and formation of lytic bone lesions. In this study, we observed the inhibitory effect of bortezomib on osteoclasts; maturation and function from peripheral blood mononuclear cells (PBMCs) of MM patients, in an attempt to clarify the upstream molecular mechanism of bortezomib on osteoclastogenesis. Osteoclast precursors from PBMCs of eight MM patients were cultured in the presence of receptor activator of NF-kappa B ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). Administration of 2.5 and 5 nM bortezomib resulted in the reduction of osteoclast differentiation by less formation of osteoclasts and the decreased activity level of TRAP. Osteoclast resorption capacity also decreased, suggesting that bortezomib was able to inhibit the function of osteoclasts. The results of Western-blot and RT-PCR assays suggested that bortezomib inhibited osteoclasts by decreasing TRAF6 production at both protein and mRNA levels. In conclusion, bortezomib acts on osteoclastgenesis at low concentrations by interfering with TRAF6 production, which might prove to be a potential strategy for the treatment of myeloma bone disease. (C) 2008 Elsevier Ltd. All rights reserved.