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

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