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 microM imatinib and lower, but was reduced by 75% at 3.0 microM imatinib. In contrast, both the area of resorption and the number of resorption lacunae were reduced by 80% at 0.3 microM imatinib, and no resorption was observed at concentrations above 3.0 microM. A dose-dependent decrease in receptor activator of nuclear factor kappaB (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.
Dewar
Andrea L
AL
Division of Haematology, Institute of Medical and Veterinary Science, Frome Rd, Adelaide 5000, Australia.
Farrugia
Amanda N
AN
Condina
Mark R
MR
Bik To
L
L
Hughes
Timothy P
TP
Vernon-Roberts
Barrie
B
Zannettino
Andrew C W
AC
D000818:Animals; D001549:Benzamides; D001847:Bone Diseases / Q000188:drug therapy*; D001862:Bone Resorption / Q000188:drug therapy / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D006023:Glycoproteins / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects; D053244:Osteoprotegerin; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors
D001549:Benzamides; D006023:Glycoproteins; D053244:Osteoprotegerin; D010879:Piperazines; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse; D000068877:Imatinib Mesylate