Sox9 Directs Hypertrophic Maturation and Blocks Osteoblast Differentiation of Growth Plate Chondrocytes

Dev Cell. 2012 Mar 13;22(3):597-609. doi: 10.1016/j.devcel.2011.12.024.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Chondrocytes / cytology
  • Chondrocytes / metabolism
  • Chondrocytes / physiology*
  • Collagen Type X / metabolism
  • Collagen Type X / physiology
  • Core Binding Factor Alpha 1 Subunit / biosynthesis
  • Female
  • Growth Plate / growth & development
  • Growth Plate / metabolism
  • Growth Plate / physiology*
  • MEF2 Transcription Factors
  • Male
  • Mice
  • Mice, Transgenic
  • Myogenic Regulatory Factors / metabolism
  • Myogenic Regulatory Factors / physiology
  • Osteoblasts / metabolism
  • Osteoblasts / physiology*
  • Osteogenesis / physiology
  • SOX9 Transcription Factor / metabolism
  • SOX9 Transcription Factor / physiology*
  • beta Catenin / metabolism
  • beta Catenin / physiology

Substances

  • CTNNB1 protein, mouse
  • Col10a1 protein, mouse
  • Collagen Type X
  • Core Binding Factor Alpha 1 Subunit
  • MEF2 Transcription Factors
  • Mef2c protein, mouse
  • Myogenic Regulatory Factors
  • Runx2 protein, mouse
  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • beta Catenin