Roles of Runx2 in Skeletal Development.

Runx2 is the most upstream transcription factor essential for osteoblast differentiation. It regulates the expression of Sp7, the protein of which is a crucial transcription factor for osteoblast differentiation, as well as that of bone matrix genes including Spp1, Ibsp, and Bglap2. Runx2 is also required for chondrocyte maturation, and Runx3 has a redundant function with Runx2 in chondrocyte maturation. Runx2 regulates the expression of Col10a1, Spp1, Ibsp, and Mmp13 in chondrocytes. It also inhibits chondrocytes from acquiring the phenotypes of permanent cartilage chondrocytes. It regulates chondrocyte proliferation through the regulation of Ihh expression. Runx2 enhances osteoclastogenesis by regulating Rankl. Cbfb, which is a co-transcription factor for Runx family proteins, plays an important role in skeletal development by stabilizing Runx family proteins. In Cbfb isoforms, Cbfb1 is more potent than Cbfb2 in Runx2-dependent transcriptional regulation; however, the expression level of Cbfb2 is three-fold higher than that of Cbfb1, demonstrating the requirement of Cbfb2 in skeletal development. The expression of Runx2 in osteoblasts is regulated by a 343-bp enhancer located upstream of the P1 promoter. This enhancer is activated by an enhanceosome composed of Dlx5/6, Mef2, Tcf7, Ctnnb1, Sox5/6, Smad1, and Sp7. Thus, Runx2 is a multifunctional transcription factor that is essential for skeletal development, and Cbfb regulates skeletal development by modulating the stability and transcriptional activity of Runx family proteins.