Direct conversion of tenocytes into chondrocytes by Sox9

Exp Cell Res. 2012 Aug 1;318(13):1492-507. doi: 10.1016/j.yexcr.2012.04.002. Epub 2012 Apr 10.

Abstract

Sox9 is a high-mobility group box-containing transcription factor that functions as a key regulator of chondrogenesis. We here report that Sox9 mediates the direct conversion of tenocytes to chondrocytes through an intermediate state in which both differentiation programs are active. Sox9 is abundantly expressed in cartilage but is undetectable in limb tendons that express Scleraxis (Scx) and Tenomodulin (Tnmd), tendon-specific early and late molecular markers, respectively. Upon forced expression of Sox9 in the chick forelimb, ectopic cartilage formation is preferentially observed in fibrous tissues including the tendons, ligaments, perichondrium/periosteum, dermis, and muscle connective tissues. Tnmd expression in tenocytes isolated from leg tendons was markedly upregulated by forced expression of basic helix-loop-helix (b-HLH) activators including Scx, Paraxis, Twist1 and Twist2. In contrast, the overexpression of Sox9 in monolayer tenocytes resulted in the downregulation of Tnmd and Scx expressions during passaging in culture, and the induction of cartilage molecular markers such as type II collagen (Col2a1) and Chondromodulin-I (ChM-I). This Sox9-driven switching from a tenocytic to a chondrocytic gene expression profile was associated with a dramatic change from a spindle to a polygonal cellular morphology. The extracellular accumulation of cartilage-characteristic proteoglycans was also observed. These data suggest that tenocytes have a strong potential for conversion into chondrocytes through the activities of Sox9 both in vitro and in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Avian Proteins / genetics
  • Avian Proteins / metabolism*
  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cell Transdifferentiation / genetics
  • Cell Transdifferentiation / physiology*
  • Cells, Cultured
  • Chick Embryo
  • Chondrocytes / cytology*
  • Chondrocytes / metabolism*
  • Chondrogenesis / genetics
  • Chondrogenesis / physiology
  • Choristoma / genetics
  • Choristoma / metabolism
  • Choristoma / pathology
  • DNA Primers / genetics
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression Regulation, Developmental
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myoblasts / cytology
  • Myoblasts / metabolism
  • Osteoblasts / cytology
  • Osteoblasts / metabolism
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism*
  • Tendons / cytology*
  • Tendons / metabolism*

Substances

  • Avian Proteins
  • Basic Helix-Loop-Helix Transcription Factors
  • DNA Primers
  • Membrane Proteins
  • SCX protein, Gallus gallus
  • SOX9 Transcription Factor