The tyrosine kinase inhibitor GNF-2 suppresses osteoclast formation and activity. Issue 2 (15th October 2013)

• Record Type: Journal Article
• Authors: Kim, Hyun-Ju; Yoon, Hye-Jin; Choi, Je-Yong; Lee, In-Kyu; Kim, Shin-Yoon
• Is Part Of: Journal of leukocyte biology. Volume 95:Issue 2(2014)
• Page Start: 337
• Page End: 345
• Publication Date: 2013-10-15
• Subjects: osteoporosis -- NF-κB -- c-Fos -- c-Fms -- LPS; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1189/jlb.0713356
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract : GNF-2 may have potential for the treatment of inflammatory bone destruction characterized by increased osteoclast number and/or 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.