Imatinib as a potential antiresorptive therapy for bone disease

Osteoclasts (OCs) are large multinucleated cells derived from progenitor cells of the monocyte-macrophage lineage. Signal transduction via the macrophage-colony-stimulating factor (M-CSF) receptor, c-fms, is essential for OC formation. Since we have previously demonstrated inhibition of c-fms by imatinib, we examined the effect of imatinib on OC formation and activity. OC formation was not affected by concentrations of 1.0 mu M imatinib and lower, but was reduced by 75% at 3.0 mu M imatinib. In contrast, both the area of resorption and the number of resorption lacunae were reduced by 80% at 0.3 mu M imatinib, and no resorption was observed at concentrations above 3.0 mu M. A dose-dependent decrease in receptor activator of nuclear factor kappa B (RANK) expression was observed in OCs when cultured in the presence of imatinib, providing 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 activity. These results suggest that imatinib may have therapeutic value as an antiosteolytic agent in diseases such as osteoporosis, metastatic bone disease, and multiple myeloma.