title: The tyrosine kinase inhibitor GNF-2 suppresses osteoclast formation and activity.
abstract: GNF-2, a tyrosine kinase inhibitor, was developed to overcome imatinib-resistant mutations found in CML patients. Osteoclasts are the principal bone-resorbing cells that are responsible for bone diseases, such as osteoporosis, tumor-induced osteolysis, and metastatic cancers. In this study, we investigated the effect of GNF-2 on osteoclast development induced by RANKL and M-CSF. We found that GNF-2 inhibited osteoclast differentiation from BMMs. GNF-2 suppressed RANKL-induced NF-κB transcriptional activity and the induction of c-Fos and NFATc1, which are two key transcription factors in osteoclastogenesis. We also observed that GNF-2 dose-dependently inhibited the proliferation of osteoclast precursors through the suppression of the M-CSFR c-Fms. In addition, GNF-2 accelerated osteoclast apoptosis by inducing caspase-3 and Bim expression. Furthermore, GNF-2 interfered with actin cytoskeletal organization and subsequently blocked the bone-resorbing activity of mature osteoclasts. In agreement with its in vitro effects, GNF-2 reduced osteoclast number and bone loss in a mouse model of LPS-induced bone destruction. Taken together, our data reveal that GNF-2 possesses anti-bone-resorptive properties, suggesting that GNF-2 may have therapeutic value for the treatment of bone-destructive disorders that can occur as a result of excessive osteoclastic bone resorption.
authors.affiliation: 1.Kyungpook National University and Hospital, 44-2 Samduk 2-ga, Jung-gu, Daegu 700-412, South Korea. biohjk@hanmail.net (H.-J. Kim) or syukim@knu.ac.kr (S.-Y. Kim).
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Kim
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Yoon
authors.forename: Je-Yong
authors.initials: JY
authors.lastname: Choi
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.forename: Shin-Yoon
authors.initials: SY
authors.lastname: Kim
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000473:pathology; D001862:Bone Resorption / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000068877:Imatinib Mesylate; D007249:Inflammation / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D053245:RANK Ligand / Q000494:pharmacology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D001549:Benzamides; C508526:GNF-2 compound; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D011743:Pyrimidines; D053245:RANK Ligand; D000068877:Imatinib Mesylate; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: LPS; NF-κB; c-Fms; c-Fos; osteoporosis