Imatinib mesylate (Gleevec) enhances mature osteoclast apoptosis and suppresses osteoclast bone resorbing activity.
Recent studies have reported that imatinib mesylate, a kinase inhibitor that targets the intracellular tyrosine kinase BCR-ABL and the platelet derived growth factor (PDGF) receptor, is an effective inhibitor of the macrophage colony stimulating factor (M-CSF) receptor, c-FMS. Given that M-CSF signalling through c-FMS plays an important role in osteoclast biology, we speculated that blocking such a pathway with imatinib may modulate osteoclast activity. Using a cell model of mature rabbit osteoclasts, we thus investigated the effect of imatinib on in vitro osteoclast apoptosis and bone resorbing activity. Our findings demonstrate that imatinib dose-dependently stimulates osteoclast apoptosis, a phenomenon which is blocked by the caspase I inhibitor Z-VAD-fmk. The ability of imatinib to enhance osteoclast cell death was accompanied by a dose-dependent inhibition of osteoclast bone resorbing activity. Imatinib was also found to inhibit M-CSF-induced osteoclast survival as well as M-CSF-induced osteoclast bone resorbing activity, but was without effect on interleukin 1alpha (IL-1alpha) and receptor activator of nuclear factor kappa B ligand (RANKL)-induced inhibition of osteoclasts apoptosis, further supporting the hypothesis that imatinib may affect mature osteoclasts through the inhibition of c-FMS. Taken together, these results suggest that imatinib could be of clinical value in treating diseases where bone destruction can occur due to excessive M-CSF production such as osteoporosis, inflammatory-and tumor-induced osteolysis.
El Hajj Dib
Iman
I
Laboratoire de Biologie et Pharmacie Clinique, UPRES-EA 2086 and INSERM ERI-12, Faculty of Pharmacie, 1, rue des Louvels, 80037 Amiens Cedex, France.
Gallet
Marlène
M
Mentaverri
Romuald
R
Sévenet
Nicolas
N
Brazier
Michel
M
Kamel
Said
S
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D016723:Bone Remodeling / Q000187:drug effects*; D001862:Bone Resorption / Q000517:prevention & control*; D061945:Caspase Inhibitors; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000068877:Imatinib Mesylate; D053582:Interleukin-1alpha / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D053245:RANK Ligand / Q000494:pharmacology; D011817:Rabbits; D013997:Time Factors
D000590:Amino Acid Chloromethyl Ketones; D001549:Benzamides; D050071:Bone Density Conservation Agents; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D053582:Interleukin-1alpha; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D053245:RANK Ligand; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D016173:Macrophage Colony-Stimulating Factor; D000068877:Imatinib Mesylate