Regulation of bone development and maintenance by Runx2

Runx2 and Sp7/Osterix determine the osteoblast lineage from mesenchymal stem cells with canonical Wnt signaling. In the process of osteoblast differentiation, these factors and canonical Wnt signaling molecules inhibit mesenchymal cells from differentiating into chondrocytes and adipocytes. After the commitment to osteoblast lineage, Runx2 maintains the osteoblasts in an immature stage, during which immature bone forms with randomly and loosely packed collagen fibrils and low mineralization. Runx2 must be suppressed for immature osteoblasts to become fully mature osteoblasts, which form mature bone with regularly and densely packed collagen fibrils and high mineralization. During the early stage of osteoblast differentiation, Runx2 regulates the expression of major bone matrix protein genes. However, Runx2 is not essential for the maintenance of the expression of the major bone matrix protein genes in mature osteoblasts. Estrogen and parathyroid hormone (PTH) enhance Runx2 expression and activity through anabolic effects, however, estrogen negatively regulates Runx2 in osteoclastogenesis. Runx2 is also involved in the catabolic effect of PTH through the induction of Tnfsf11. Thus, Runx2 regulates bone development, bone maturation, and bone maintenance through the regulation of osteoblast differentiation and function.