Runx2 and Runx3 are essential for chondrocyte maturation, and Runx2 regulates limb growth through induction of Indian hedgehog

  1. Carolina A. Yoshida1,2,7,
  2. Hiromitsu Yamamoto3,7,
  3. Takashi Fujita4,
  4. Tatsuya Furuichi1,
  5. Kosei Ito5,
  6. Ken-ichi Inoue5,
  7. Kei Yamana6,
  8. Akira Zanma1,6,
  9. Kenji Takada2,
  10. Yoshiaki Ito5, and
  11. Toshihisa Komori1,8
  1. 1Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; 2Department of Orthodontics and Dentofacial Orthopedics, Osaka University Faculty of Dentistry, Suita, Osaka 565-0871, Japan; 3Department of Oral and Maxillofacial Surgery, Graduate School of Medicine, Kyoto University, Sakyo, Kyoto 606-8507, Japan; 4Department of Pharmacology, Faculty of Pharmaceutical Science, Setsunan University, Hirakata, Osaka, Japan; 5Insitute of Molecular and Cell Biology, Singapore 117609, Singapore; 6Teijin Institute for Biomedical Research, Teijin Ltd., Hino, Tokyo 191-8512, Japan

Abstract

The differentiation of mesenchymal cells into chondrocytes and chondrocyte proliferation and maturation are fundamental steps in skeletal development. Runx2 is essential for osteoblast differentiation and is involved in chondrocyte maturation. Although chondrocyte maturation is delayed in Runx2-deficient (Runx2–/–) mice, terminal differentiation of chondrocytes does occur, indicating that additional factors are involved in chondrocyte maturation. We investigated the involvement of Runx3 in chondrocyte differentiation by generating Runx2-and-Runx3-deficient (Runx2–/–3–/–) mice. We found that chondrocyte differentiation was inhibited depending on the dosages of Runx2 and Runx3, and Runx2–/–3–/– mice showed a complete absence of chondrocyte maturation. Further, the length of the limbs was reduced depending on the dosages of Runx2 and Runx3, due to reduced and disorganized chondrocyte proliferation and reduced cell size in the diaphyses. Runx2–/–3–/– mice did not express Ihh, which regulates chondrocyte proliferation and maturation. Adenoviral introduction of Runx2 in Runx2–/– chondrocyte cultures strongly induced Ihh expression. Moreover, Runx2 directly bound to the promoter region of the Ihh gene and strongly induced expression of the reporter gene driven by the Ihh promoter. These findings demonstrate that Runx2 and Runx3 are essential for chondrocyte maturation and that Runx2 regulates limb growth by organizing chondrocyte maturation and proliferation through the induction of Ihh expression.

Keywords

Footnotes

  • Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1174704.

  • 7 These authors contributed equally to this work.

  • 8 Corresponding author.

    8 E-MAIL komorit{at}imed3.med.osaka-u.ac.jp; FAX 81-6-6879-7796.

    • Accepted March 11, 2004.
    • Received December 2, 2003.
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