Fig. 2. Regulation of the proliferation and differentiation of osteoblast-lineage cells by Runx2.

Ihh is required for Runx2 expression, and hedgehog signaling and Runx2 induce the differentiation of multipotent mesenchymal cells into preosteoblasts in endochondral bone. Runx2 activates the hedgehog signaling pathway through the induction of Ihh, Gli1, and Ptch1. Runx2, Sp7, and the canonical Wnt signaling pathway induce the differentiation of preosteoblasts into immature osteoblasts. Runx2 induces Sp7 expression at the preosteoblast stage, Runx2 activates the Wnt signaling pathway through the induction of Tcf7 and Wnt10b expression, and Sp7 and Tcf7 activate a Runx2 enhancer. Runx2 and Sp7 induce the differentiation of immature osteoblasts into mature osteoblasts. Runx2 induces the proliferation of multipotent mesenchymal cells, osteoprogenitors, and preosteoblasts through the regulation of Fgf, hedgehog, Wnt, and Pthlh signaling pathway genes. The mutual regulation between Runx2 and the signaling pathways, including hedgehog, Fgf, Wnt, and Pthlh, or Sp7 plays important roles in the proliferation and differentiation of osteoblast-lineage cells and their progenitors.