Effects of Vitaxin on hyperactive osteoclastogenesis in multiple myeloma: A preclinical study.

Abstract

e18501 Background: Myeloma bone disease (MBD) is characterized by progressive skeleton destruction as effect of accelerated marrow osteoclast (OC) differentiation induced by malignant plasma cells. Myeloma cells, however, exert bone resorptive activity in vitro and OC-like plasma cell polykaryons, are also detectable in vivo in osteolytic lesions. We demonstrated that, similarly to OCs, this property in myeloma cells is dependent on the avb3 integrin, in particular b3 chain, since b3-silenced myeloma cells fail to produce experimental bone erosions. The MoAb Vitaxin (LM609 anti-avb3) was proved to restrain the OC activity in bone metastases from solid tumors. Thus, we explored its effect on bone resorbing malignant plasma cells. Methods: Nine avb3+ myeloma cell lines from patients with MBD were incubated for 48 hr on both calcium phosphate and dentine slices. Five OC preparations from normal macrophages served as controls. Parallel cell preparations were conditioned by Vitaxin and the bone resorption was calculated as both number and area of the erosive pits. Phosphorylation of ERK1/2 induced by avb3 in activated OCs, was also measured by western blot. Results: All myelomas variably produced extensive erosion in vitro whose total value was 10-15% lower than control OCs. However, Vitaxin significantly suppressed this activity. Maximal inhibition was observed by 300 ng/ml which provided the full suppression in four instances whereas a residual activity no higher than 3-5% of the unconditioned controls was revealed in the other myeloma cell lines. Furthermore, in Vitaxin-treated myelomas, phosphorylated ERK1/2 was undetectable by western blot, as in control OCs. Conclusions: By blocking avb3, Vitaxin prevents the ERK1/2 phosphorylation leading to the OC-like activities. Thus, our data suggest that this MoAb is apparently effective in disabling the erosive function of both myeloma cells and OCs in vitro, suggesting its potential use in vivo in future treatments of MBD. No significant financial relationships to disclose.