Imatinib as a potential antiresorptive therapy for bone disease

Abstract

From the Myeloma and Mesenchymal Research Laboratory, the Division of Haematology, Level 2 Hanson Institute, and the Adelaide Centre for Spinal Research, Institute of Medical and Veterinary Science (IMVS), Adelaide, South Australia, Australia. 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 µM imatinib and lower, but was reduced by 75% at 3.0 µM imatinib. In contrast, both the area of resorption and the number of resorption lacunae were reduced by 80% at 0.3 µM imatinib, and no resorption was observed at concentrations above 3.0 µM. A dose-dependent decrease in receptor activator of nuclear factor 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.