HEMATOPOIESIS Imatinib as a potential antiresorptive therapy for bone disease

Osteoclasts (OCs) are large multinucle-ated cells derived from progenitor cells of the monocyte-macrophage lineage. Sig-nal transduction via the macrophage– colony-stimulating factor (M-CSF) recep-tor, c-fms, is essential for OC formation. Since we have previously demonstrated inhibition of c-fms by imatinib, we exam-ined the effect of imatinib on OC forma-tion and activity. OC formation was not affected by concentrations of 1.0 M ima-tinib and lower, but was reduced by 75% at 3.0 M imatinib. In contrast, both the area of resorption and the number of resorption lacunae were reduced by 80% at 0.3 M imatinib, and no resorption was observed at concentrations above 3.0M. A dose-dependent decrease in receptor activator of nuclear factor B (RANK) expression was observed in OCs when cultured in the presence of imatinib, pro-viding a mechanism for the decrease in OC function. In vivo analysis of the effect of imatinib on OC activity in adult mice following 8 weeks of imatinib treatment also demonstrated a decrease in OC activ-ity. These results suggest that imatinib may have therapeutic value as an antios-teolytic agent in diseases such as osteo-porosis, metastatic bone disease, and multiple myeloma. (Blood. 2006;107