title: Filamin B represses chondrocyte hypertrophy in a Runx2/Smad3-dependent manner.
abstract: FILAMIN B, which encodes a cytoplasmic actin binding protein, is mutated in several skeletal dysplasias. To further investigate how an actin binding protein influences skeletogenesis, we generated mice lacking intact Filamin B. As observed in spondylocarpotarsal synostosis syndrome patients, Filamin B mutant mice display ectopic mineralization in many cartilaginous elements. This aberrant mineralization is due to ectopic chondrocyte hypertrophy similar to that seen in mice expressing Runx2 in chondrocytes. Accordingly, removing one copy of Runx2 rescues the Filamin B mutant phenotype, indicating that Filamin B is a regulator of Runx2 function during chondrocyte differentiation. Filamin B binds Smad3, which is known to interact with Runx2. Smad3 phosphorylation is increased in the mutant mice. Thus, Filamin B inhibits Runx2 activity, at least in part, through the Smad3 pathway. Our results uncover the involvement of actin binding proteins during chondrogenesis and provide a molecular basis to a human genetic disease.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Zheng
authors.forename: Hwa-Jin
authors.initials: HJ
authors.lastname: Baek
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Justice
mesh_terms: D000818:Animals; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology*; D003285:Contractile Proteins / Q000172:deficiency* / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism*; D064448:Filamins; D018507:Gene Expression Regulation, Developmental; D005982:Glutathione Transferase / Q000378:metabolism; D006984:Hypertrophy; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000172:deficiency* / Q000235:genetics; D008954:Models, Biological; D009154:Mutation; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism*
chemical_list: D003285:Contractile Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D064448:Filamins; D008840:Microfilament Proteins; D011994:Recombinant Proteins; C493716:Runx2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D005982:Glutathione Transferase