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Loss of Foxc1 and Foxc2 function in chondroprogenitor cells disrupts endochondral ossification.
Almubarak, Asra; Lavy, Rotem; Srnic, Nikola; Hu, Yawen; Maripuri, Devi Priyanka; Kume, Tsutomo; Berry, Fred B.
Afiliación
  • Almubarak A; Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
  • Lavy R; Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
  • Srnic N; Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
  • Hu Y; Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
  • Maripuri DP; Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
  • Kume T; Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Department of Medicine, Northwestern University, Chicago, IL, USA.
  • Berry FB; Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada; Department of Surgery, University of Alberta, Edmonton, Alberta, Canada. Electronic address: fberry@ualberta.ca.
J Biol Chem ; 297(3): 101020, 2021 09.
Article en En | MEDLINE | ID: mdl-34331943
Endochondral ossification initiates the growth of the majority of the mammalian skeleton and is tightly controlled through gene regulatory networks. The forkhead box transcription factors Foxc1 and Foxc2 regulate aspects of osteoblast function in the formation of the skeleton, but their roles in chondrocytes to control endochondral ossification are less clear. Here, we demonstrate that Foxc1 expression is directly regulated by the activity of SRY (sex-determining region Y)-box 9, one of the earliest transcription factors to specify the chondrocyte lineage. Moreover, we demonstrate that elevated expression of Foxc1 promotes chondrocyte differentiation in mouse embryonic stem cells and loss of Foxc1 function inhibits chondrogenesis in vitro. Using chondrocyte-targeted deletion of Foxc1 and Foxc2 in mice, we reveal a role for these factors in chondrocyte differentiation in vivo. Loss of both Foxc1 and Foxc2 caused a general skeletal dysplasia predominantly affecting the vertebral column. The long bones of the limbs were smaller, mineralization was reduced, and organization of the growth plate was disrupted; in particular, the stacked columnar organization of the proliferative chondrocyte layer was reduced in size and cell proliferation was decreased. Differential gene expression analysis indicated disrupted expression patterns of chondrogenesis and ossification genes throughout the entire process of endochondral ossification in chondrocyte-specific Foxc1/Foxc2 KO embryos. Our results suggest that Foxc1 and Foxc2 are required for normal chondrocyte differentiation and function, as loss of both genes results in disorganization of the growth plate, reduced chondrocyte proliferation, and delays in chondrocyte hypertrophy that prevents ossification of the skeleton.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteogénesis / Células Madre / Condrocitos / Condrogénesis / Factores de Transcripción Forkhead Límite: Animals Idioma: En Revista: J Biol Chem Año: 2021 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteogénesis / Células Madre / Condrocitos / Condrogénesis / Factores de Transcripción Forkhead Límite: Animals Idioma: En Revista: J Biol Chem Año: 2021 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos