title: The distinct role of the Runx proteins in chondrocyte differentiation and intervertebral disc degeneration: findings in murine models and in human disease.
abstract: OBJECTIVE
  Runx2 is a transcription factor that regulates chondrocyte differentiation. This study was undertaken to address the role of the different Runx proteins (Runx1, Runx2, or Runx3) in chondrocyte differentiation using chondrocyte-specific Runx-transgenic mice, and to study the importance of the QA domain of Runx2, which is involved in its transcriptional activation.
  
  
  METHODS
  Runx expression was analyzed in the mouse embryo by in situ hybridization. Overexpression of Runx1, Runx2 (lacking the QA domain [DeltaQA]), or Runx3 was induced in chondrocytes in vivo, to produce alpha(1)II-Runx1, alpha(1)II-Runx2DeltaQA, and alpha(1)II-Runx3 mice, respectively, for histologic and molecular analyses. Runx expression was also examined in an experimental mouse model of mechanical stress-induced intervertebral disc (IVD) degeneration and in human patients with IVD degeneration.
  
  
  RESULTS
  Runx1 expression was transiently observed in condensations of mesenchymal cells, whereas Runx2 and Runx3 were robustly expressed in prehypertrophic chondrocytes. Similar to alpha(1)II-Runx2 mice, alpha(1)II-Runx2DeltaQA and alpha(1)II-Runx3 mice developed ectopic mineralization of cartilage, but this was less severe in the alpha(1)II-Runx2DeltaQA mice. In contrast, alpha(1)II-Runx1 mice displayed no signs of ectopic mineralization. Surprisingly, alpha(1)II-Runx1 and alpha(1)II-Runx2 mice developed scoliosis due to IVD degeneration, characterized by an accumulation of extracellular matrix and ectopic chondrocyte hypertrophy. During mouse embryogenesis, Runx2, but not Runx1 or Runx3, was expressed in the IVDs. Moreover, both in the mouse model of IVD degeneration and in human patients with IVD degeneration, there was significant up-regulation of Runx2 expression.
  
  
  CONCLUSIONS
  Each Runx protein has a distinct, yet overlapping, role during chondrocyte differentiation. Runx2 contributes to the pathogenesis of IVD degeneration.
authors.affiliation: Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Sato
authors.forename: Ayako
authors.initials: A
authors.lastname: Kimura
authors.forename: Jerfi
authors.initials: J
authors.lastname: Ozdemir
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Asou
authors.forename: Makiko
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Jinno
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ae
authors.forename: Xiuyun
authors.initials: X
authors.lastname: Liu
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Osaki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Seiji
authors.initials: S
authors.lastname: Fukumoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawaguchi
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Haro
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Shinomiya
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
authors.forename: Shu
authors.initials: S
authors.lastname: Takeda