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-kappaB ligand (RANKL) and macrophage-colony stimulating factor (M-CSF). Administration of 2.5 and 5nM 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.
Hongming
Huang
H
Department of Hematology, Changzheng Hospital, The Second Hospital Affiliated to The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
Jian
Hou
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002454:Cell Differentiation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects*; D009101:Multiple Myeloma / Q000473:pathology*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology*; D053245:RANK Ligand / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048029:TNF Receptor-Associated Factor 6 / Q000502:physiology*
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D053245:RANK Ligand; D048029:TNF Receptor-Associated Factor 6; C505688:TNFSF11 protein, human; D000069286:Bortezomib; D016173:Macrophage Colony-Stimulating Factor