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Fig. 1. Regulation of the proliferation and differentiation of chondrocytes by Runx2. The growth plate is composed of the resting and proliferating chondrocyte layers, which express Col2a1, prehypertrophic chondrocyte layer, which expresses Ihh and Pth1r, hypertrophic chondrocyte layer, which expresses Col10a1, and terminal hypertrophic chondrocyte layer, which expresses Spp1, Ibsp, Mmp13, and Vegfa. Runx2 expression is upregulated in the prehypertrophic chondrocyte layer and induces their maturation into hypertrophic chondrocytes. Runx3 is also involved in this process. Runx2 induces the expression of Ihh, which induces the proliferation of chondrocytes, and Ihh induces the expression of Pthlh, which inhibits Runx2 expression and chondrocyte maturation through Pth1r, forming a negative feedback loop. Runx2 also regulates the expression of Col10a1, Spp1, Ibsp, Mmp13, and Vegfa. Ihh induces Runx2 expression in the perichondrium for the differentiation of osteoblasts, which form the bone collar and primary spongiosa. Most terminal hypertrophic chondrocytes transdifferentiate into osteoblasts.
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