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

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: osteoporosis;    NF‐;    κ;    B;    c‐;    Fos;    c‐;    Fms;    LPS;   

DOI  :  10.1189/jlb.0713356

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 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...

【 授权许可】

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