Signaling and transcriptional regulation in osteoblast commitment and differentiation

Abstract

The major event that triggers osteogenesis is the transition of mesenchymal stem cells into bone forming, differentiating osteoblast cells. Osteoblast differentiation is the primary component of bone formation, exemplified by the synthesis, deposition and mineralization of extracellular matrix. Although not well understood, osteoblast differentiation from mesenchymal stem cells is a well-orchestrated process. Recent advances in molecular and genetic studies using gene targeting in mouse enable a better understanding of the multiple factors and signaling networks that control the differentiation process at a molecular level. Osteoblast commitment and differentiation are controlled by complex activities involving signal transduction and transcriptional regulation of gene expression. We review Wnt signaling pathway and Runx2 regulation network, which are critical for osteoblast differentiation. Many other factors and signaling pathways have been implicated in regulation of osteoblast differentiation in a network manner, such as the factors Osterix, ATF4, and SATB2 and the TGF-beta, Hedgehog, FGF, ephrin, and sympathetic signaling pathways. This review summarizes the recent advances in the studies of signaling transduction pathways and transcriptional regulation of osteoblast cell lineage commitment and differentiation. The knowledge of osteoblast commitment and differentiation should be applied towards the development of new diagnostic and therapeutic alternatives for human bone diseases.

Figure 1

Six important signaling networks of osteoblast differentiation. Binding of Wnt to the FZD receptor induces ß-catenin accumulation, which translocates to the nucleus to activate target gene transcription. Several transcription factors have been found crucial for osteoblast differentiation downstream of this signaling pathway, such as Runx2, Osterix, and ATF4. They are essential for differentiation of mesenchymal stem cells into differentiated osteoblasts and also function in the transcription of osteoclast-specific genes. The dotted lines indicate that the physiological function or the stage at which the factor mainly works remains to be proven.

Figure 2

Regulation of osteoblast differentiation by transcription factors. In osteoblast differentiation, high levels of Runx2 and ß-catenin are necessary to suppress the chondrogenic potential of uncommitted progenitors, such as the proposed osteochondroprogenitor. Osterix is required for the final commitment of progenitors to preosteoblasts. † signs indicate positive effects; ‡ signs indicate inhibitory effects.