1. Academic Validation
  2. The tyrosine kinase inhibitor GNF-2 suppresses osteoclast formation and activity

The tyrosine kinase inhibitor GNF-2 suppresses osteoclast formation and activity

  • J Leukoc Biol. 2014 Feb;95(2):337-45. doi: 10.1189/jlb.0713356.
Hyun-Ju Kim 1 Hye-Jin Yoon Je-Yong Choi In-Kyu Lee Shin-Yoon Kim
Affiliations

Affiliation

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.

Keywords

LPS; NF-κB; c-Fms; c-Fos; osteoporosis.

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