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

[摘要] GNF‐2,atyrosinekinaseinhibitor,wasdevelopedtoovercomeimatinib‐resistantmutationsfoundinCMLpatients.Osteoclastsaretheprincipalbone‐resorbingcellsthatareresponsibleforbonediseases,suchasosteoporosis,tumor‐inducedosteolysis,andmetastaticcancers.Inthisstudy,weinvestigatedtheeffectofGNF‐2onosteoclastdevelopmentinducedbyRANKLandM‐CSF.WefoundthatGNF‐2inhibitedosteoclastdifferentiationfromBMMs.GNF‐2suppressedRANKL‐inducedNF‐κBtranscriptionalactivityandtheinductionofc‐FosandNFATc1,whicharetwokeytranscriptionfactorsinosteoclastogenesis.WealsoobservedthatGNF‐2dose‐dependentlyinhibitedtheproliferationofosteoclastprecursorsthroughthesuppressionoftheM‐CSFRc‐Fms.Inaddition,GNF‐2acceleratedosteoclastapoptosisbyinducingcaspase‐3andBimexpression.Furthermore,GNF‐2interferedwithactincytoskeletalorganizationandsubsequentlyblockedthebone‐resorbingactivityofmatureosteoclasts.Inagreementwithitsinvitroeffects,GNF‐2reducedosteoclastnumberandbonelossinamousemodelofLPS‐inducedbonedestruction.Takentogether,ourdatarevealthatGNF‐2possessesanti‐bone‐resorptiveproperties,suggestingthatGNF‐2mayhavetherapeuticvalueforthetreatmentofbone‐destructivedisordersthatcanoccurasaresultofexcessiveosteoclasticboneresorption...

[学科分类] 生理学

[关键词] osteoporosis;NF‐κB;c‐Fos;c‐Fms;LPS