Imatinib as a potential antiresorptive therapy for bone disease

• Published in: Blood 2006-06, Vol.107 (11), p.4334-4337
• Main Authors: Dewar, Andrea L., Farrugia, Amanda N., Condina, Mark R., Bik To, L., Hughes, Timothy P., Vernon-Roberts, Barrie, Zannettino, Andrew C.W.
• Format: Article
• Language: English
• Subjects: Animals; Benzamides; Biological and medical sciences; Bone Diseases - drug therapy; Bone Resorption - drug therapy; Bone Resorption - prevention & control; Diseases of the osteoarticular system; Dose-Response Relationship, Drug; Glycoproteins - antagonists & inhibitors; Humans; Imatinib Mesylate; Medical sciences; Mice; Mice, Inbred BALB C; Monocytes - drug effects; Osteoclasts - drug effects; Osteoporosis. Osteomalacia. Paget disease; Osteoprotegerin; Piperazines - pharmacology; Piperazines - therapeutic use; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Tumor Necrosis Factor - antagonists & inhibitors
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-09-3568

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 κB (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.