The Wnt Antagonist Frzb-1 Regulates Chondrocyte Maturation and Long Bone Development during Limb Skeletogenesis

Developmental Biology

Philippa H. Francis-West¹  Motomi Enomoto-Iwamoto¹  Naoko Kanatani¹  Yoshihiro Tamamura¹  Hiroshi Okada¹  Eiki Koyama¹  Changshan Wu¹  Jirouta Kitagaki¹  Toshihisa Komori¹  Tsutomu Nohno¹  Toshiyuki Yoneda¹  Vicki Church¹  Masahiro Iwamoto¹  Maurizio Pacifici¹  Kojiro Kurisu¹  Tatsuya Koike¹ 

[1] Departments of Molecular, Cell and Tumor Biology, Osaka University Faculty of Dentistry, Suita, Osaka, 565-0871, Japan

关键词: Wnt signaling;    Frzb-1;    chondrocyte maturation;    matrix mineralization;    endochondral ossification;    limb development;   

DOI  :  10.1006/dbio.2002.0802

学科分类：生物科学（综合）

来源: Academic Press

【 摘 要 】

TheWntantagonistFrzb-1isexpressedduringlimbskeletogenesis,butitsrolesinthiscomplexmultistepprocessarenotfullyunderstood.Toaddressthisissue,wedeterminedFrzb-1geneexpressionpatternsduringchicklongbonedevelopmentandcarriedoutgain-andloss-of-functionstudiesbymisexpressionofFrzb-1,Wnt-8(aknownFrzb-1target),ordifferentformsoftheintracellularWntmediatorLEF-1indevelopinglimbsandculturedchondrocytes.Frzb-1expressionwasquitestronginmesenchymalprechondrogeniccondensationsandthencharacterizedepiphysealarticularchondrocytesandprehypertrophicchondrocytesingrowthplates.VirallydrivenFrzb-1misexpressioncausedshorteningofskeletalelements,jointfusion,anddelayedchondrocytematuration,withconsequentinhibitionofmatrixmineralization,metalloproteaseexpression,andmarrow/boneformation.Ingoodagreement,misexpressionofFrzb-1oradominant-negativeformofLEF-1inculturedchondrocytesmaintainedthecellsatanimmaturestage.Instead,misexpressionofWnt-8oraconstitutivelyactiveLEF-1stronglypromotedchondrocytematuration,hypertrophy,andcalcification.ImmunostainingrevealedthatthedistributionofendogenousWntmediatorβ-cateninchangesdramaticallyinvivoandinvitro,fromlargelycytoplasmicinimmatureproliferatingandprehypertrophicchondrocytestonuclearinhypertrophicmineralizingchondrocytes.MisexpressionofFrzb-1preventedβ-cateninnuclearrelocalizationinchondrocytesinvivoorinvitro.ThedatademonstratethatFrzb-1exertsastronginfluenceonlimbskeletogenesisandisapowerfulanddirectmodulatorofchondrocytematuration,phenotype,andfunction.Phasesofskeletogenesis,suchasterminalchondrocytematurationandjointformation,appeartobeparticularlydependentonWntsignalingandthusverysensitivetoFrzb-1antagonisticaction.

【 授权许可】

Unknown