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

By C. Yoshida, Hiromitsu Yamamoto, T. Fujita, T. Furuichi, Kosei Ito, Ken-ichi Inoue, K. Yamana, A. Zanma, K. Takada, Yoshiaki Ito and 1 more. Genes & Development, 2004

606 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/f8ad715ed796a9b7ca3bd90525004d445269b998

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In Molecular Biology

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Citations in the corpus

• Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. (2004, background): “Recently, the Ihh gene was shown to be a direct transcriptional target gene of Runx2 (Yoshida et al., 2004).”
• Development of the endochondral skeleton. (2013, background): “The role of RUNX2 in chondrocyte hypertrophy appears to be shared with RUNX3, as simultaneous deletion of both completely blocked hypertrophy in all endochondral skeletal elements (Yoshida et al. 2004).”
• Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. (2005, background): “Both transcription factors, Runx2 and Osx, are also expressed in prehypertrophic and hypertrophic chondrocytes, but only Runx2 is required for chondrogenesis (Inada et al., 1999; Kim et al., 1999; Nakashima et al., 2002; Yoshida et al., 2004; Zelzer et al., 2001).”
• Regulation of Proliferation, Differentiation and Functions of Osteoblasts by Runx2 (2019, background): “Runx2–/–Runx3–/– mice lack hypertrophic chondrocytes, suggesting that Runx2 and Runx3 have redundant functions in chondrocyte maturation [12].”
• Regulation of bone development and extracellular matrix protein genes by RUNX2 (2009, background): “RUNX2 and RUNX3 have redundant functions in chondrocyte maturation, and chondrocyte maturation is completely inhibited in whole skeletons of Runx2−/−Runx3−/− mice (Yoshida et al. 2004).”