In addition to regulating osteoblast differentiation, RUNX2 regulates skeletal development by regulating maturation of chondrocytes (Takeda et al. 2001). Chondrocyte maturation happens during the process of endochondral ossification. Expression of the parathyroid hormone receptor (PTHR1) and Indian hedgehog (IHH) are hallmarks of chondrocyte maturation. Mice that are double knockouts for Runx2 and Runx3 show a complete absence of chondrocyte maturation and, hence, aberrant limb growth. Based on mouse studies, RUNX2 directly regulates transcription of the IHH gene. RUNX2 binding sites in the IHH gene promoter are conserved in humans (Yoshida et al. 2004). Also based on mouse studies, RUNX2 positively regulates transcription of NELL1 (neural EGFL-like 1), a key functional mediator of chondrogenesis, but direct binding of RUNX2 to the NELL1 gene locus has not been demonstrated (Li et al. 2017). Runx2 binding sites exist in the enhancer of the mouse Col10a1 gene, encoding type X collagen, a marker of hypertrophic chondrocytes, which is critical for endochondral bone formation. While Runx2 binding is required, it is not sufficient to trigger Col10a1 transcription (Gu et al. 2014).
Gu, J, Wang, Q, Lei, G, Lu, Y, Borgia, JA, Li, N, Qiao, L, Li, F, Zheng, Q, Deng, Y
Zhou, Y, Li, C, Chen, E, Chen, X, Soo, C, Zheng, Z, Jiang, J, Culiat, CT, Qiao, Y, Ting, K, Zhang, X, Lee, KS
Owen, MJ, Takeda, S, Karsenty, G, Ducy, P, Bonnamy, JP
Ito, Y, Fujita, T, Komori, T, Inoue, K, Takada, K, Yoshida, CA, Furuichi, T, Yamamoto, H, Zanma, A, Ito, K, Yamana, K
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