The functions of Runx family transcription factors and Cbfb in skeletal development

Abstract

Runx family transcription factors consist of Runx1, Runx2, and Runx3. Runx1 is involved in chondrocyte differentiation at an early stage. Runx2 is a major transcription factor for chondrocyte maturation, and Runx3 has a redundant function with Runx2 and it is partly involved in chondrocyte maturation. Runx2 directly regulates Ihh expression and enhances chondrocyte proliferation. Runx2 is an essential transcription factor for osteoblast differentiation. Heterozygous mutation of RUNX2 causes cleidocranial dysplasia, which is characterized by hypoplastic clavicles, open fontanelles, and supernumerary teeth. Runx2 directly regulates Sp7 expression, and Runx2 together with Sp7 and canonical Wnt signaling completes determination of the lineage of mesenchymal cells into osteoblasts. Runx2 expression in osteoblasts is regulated by a 343-bp enhancer. Dlx5/6 and Mef2 directly bind this enhancer; form an enhanceosome with Tcf7, β-catenin, Sox5/6, Smad1, and Sp7; and activate this enhancer. Msx2 inhibits this enhancer, and switching of the binding of Msx2 to Dlx5 is important for this activation. Core binding factor β (Cbfb) forms a heterodimer with Runx family proteins and enhances their DNA-binding capacity. In Cbfb conditional knockout mice in osteoblast and chondrocyte lineages, the differentiation of chondrocytes and osteoblasts is inhibited. All of the Runx family proteins are reduced in the cartilaginous limb skeletons and calvariae in Cbfb conditional knockout mice, although the reduction of Runx2 protein in calvariae is much milder than that in cartilaginous limb skeletons. Therefore, Cbfb regulates skeletal development by stabilizing Runx family proteins, and Runx2 protein stability is less dependent on Cbfb in calvariae than in cartilaginous limb skeletons.