The Tyrosine Kinase Inhibitor Dasatinib Dysregulates Bone Remodeling Through Inhibition of Osteoclasts In Vivo
Kate Vandyke, Andrea L Dewar, Peter Diamond, Stephen Fitter, Christopher G Schultz, Natalie A Sims, Andrew CW Zannettino
JOURNAL OF BONE AND MINERAL RESEARCH | WILEY | Published : 2010
Dasatinib is a potent tyrosine kinase inhibitor that is used to treat chronic myeloid leukemia in patients resistant or intolerant to imatinib mesylate. While designed to inhibit Abl and Src kinases, dasatinib shows multitarget effects, including inhibition of the macrophage colony-stimulating factor (M-CSF) receptor c-fms. We have shown previously that dasatinib abrogates osteoclast formation and activity in vitro owing, in part, to its specificity for c-fms. In this study we examined whether dasatinib could significantly alter bone volume in a model of physiologic bone turnover. Sprague-Dawley rats were administered dasatinib (5 mg/kg/day) or vehicle by gavage or zoledronic acid (ZOL; 100 ..View full abstract
We are grateful to Behzad Baradaran and the staff at Veterinary Services, IMVS, for their assistance with the animal experiments. We wish to thank Lee Anne Griffiths, Francis Lee, Richard Smykla, and Kate Church from Bristol-Myers Squibb for providing the dasatinib and helpful discussions. This work is supported by a grant from the Leukemia and Lymphoma Society Translational Research Program (awarded to ACWZ).