title: Sox9 directs hypertrophic maturation and blocks osteoblast differentiation of growth plate chondrocytes.
abstract: The transcription factor Sox9 is necessary for early chondrogenesis, but its subsequent roles in the cartilage growth plate, a highly specialized structure that drives skeletal growth and endochondral ossification, remain unclear. Using a doxycycline-inducible Cre transgene and Sox9 conditional null alleles in the mouse, we show that Sox9 is required to maintain chondrocyte columnar proliferation and generate cell hypertrophy, two key features of functional growth plates. Sox9 keeps Runx2 expression and β-catenin signaling in check and thereby inhibits not only progression from proliferation to prehypertrophy, but also subsequent acquisition of an osteoblastic phenotype. Sox9 protein outlives Sox9 RNA in upper hypertrophic chondrocytes, where it contributes with Mef2c to directly activate the major marker of these cells, Col10a1. These findings thus reveal that Sox9 remains a central determinant of the lineage fate and multistep differentiation program of growth plate chondrocytes and thereby illuminate our understanding of key molecular mechanisms underlying skeletogenesis.
authors.affiliation: Department of Cell Biology, Orthopaedic and Rheumatologic Research Center, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Dy
authors.forename: Weihuan
authors.initials: W
authors.lastname: Wang
authors.forename: Pallavi
authors.initials: P
authors.lastname: Bhattaram
authors.forename: Qiuqing
authors.initials: Q
authors.lastname: Wang
authors.forename: Lai
authors.initials: L
authors.lastname: Wang
authors.forename: R Tracy
authors.initials: RT
authors.lastname: Ballock
authors.forename: Véronique
authors.initials: V
authors.lastname: Lefebvre
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D024121:Collagen Type X / Q000378:metabolism / Q000502:physiology; D050659:Core Binding Factor Alpha 1 Subunit / Q000096:biosynthesis; D005260:Female; D006132:Growth Plate / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018006:Myogenic Regulatory Factors / Q000378:metabolism / Q000502:physiology; D010006:Osteoblasts / Q000378:metabolism / Q000502:physiology*; D010012:Osteogenesis / Q000502:physiology; D055758:SOX9 Transcription Factor / Q000378:metabolism / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism / Q000502:physiology
chemical_list: C495267:CTNNB1 protein, mouse; C570620:Col10a1 protein, mouse; D024121:Collagen Type X; D050659:Core Binding Factor Alpha 1 Subunit; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; C493716:Runx2 protein, mouse; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D051176:beta Catenin