Multiple myeloma cells directly stimulate bone resorption in vitro by down-regulating mature osteoclast apoptosis.

Multiple myeloma (MM) is characterized by devastating bone destruction mainly due to stimulation of osteoclastogenesis. However, whether MM cells can directly influence osteoclast apoptosis, a mechanism that would contribute to increase the number of active osteoclasts, has not been addressed yet. Herein, using authentic mature rabbit osteoclasts, we demonstrated that conditioned media (CM) prepared from U266 and RPMI8226 cells but not from LP-1 and OPM-2 cells, stimulated bone resorption and inhibited osteoclast apoptosis in a dose-dependent manner. The MM cells which exerted an anti-apoptotic effect secreted high amounts of M-CSF and addition of a neutralizing antibody against M-CSF reversed the CM effects. Imatinib mesylate, a tyrosine kinase inhibitor that can target the M-CSF receptor, also prevented the effect of CM. These findings suggest that M-CSF originating from MM cells may play a critical role in MM bone disease by decreasing osteoclast apoptosis.

Imatinib mesylate (Gleevec) enhances mature osteoclast apoptosis and suppresses osteoclast bone resorbing activity.

Recent studies have reported that imatinib mesylate, a kinase inhibitor that targets the intracellular tyrosine kinase BCR-ABL and the platelet derived growth factor (PDGF) receptor, is an effective inhibitor of the macrophage colony stimulating factor (M-CSF) receptor, c-FMS. Given that M-CSF signalling through c-FMS plays an important role in osteoclast biology, we speculated that blocking such a pathway with imatinib may modulate osteoclast activity. Using a cell model of mature rabbit osteoclasts, we thus investigated the effect of imatinib on in vitro osteoclast apoptosis and bone resorbing activity. Our findings demonstrate that imatinib dose-dependently stimulates osteoclast apoptosis, a phenomenon which is blocked by the caspase I inhibitor Z-VAD-fmk. The ability of imatinib to enhance osteoclast cell death was accompanied by a dose-dependent inhibition of osteoclast bone resorbing activity. Imatinib was also found to inhibit M-CSF-induced osteoclast survival as well as M-CSF-induced osteoclast bone resorbing activity, but was without effect on interleukin 1alpha (IL-1alpha) and receptor activator of nuclear factor kappa B ligand (RANKL)-induced inhibition of osteoclasts apoptosis, further supporting the hypothesis that imatinib may affect mature osteoclasts through the inhibition of c-FMS. Taken together, these results suggest that imatinib could be of clinical value in treating diseases where bone destruction can occur due to excessive M-CSF production such as osteoporosis, inflammatory-and tumor-induced osteolysis.