Transcriptional regulatory cascades in Runx2-dependent bone development

Abstract

The development of the musculoskeletal system is a complex process that involves very precise control of bone formation and growth as well as remodeling during postnatal life. Although the understanding of the transcriptional mechanisms of osteogenesis has increased considerably, the molecular regulatory basis, especially the gene regulatory network of osteogenic differentiation, is still poorly understood. This review provides the reader with an overview of the key transcription factors that govern bone formation, highlighting their function and regulation linked to Runt-related transcription factor 2 (Runx2). Runx2 as the master transcription factor of osteoblast differentiation, Twist, Msh homeobox 2 (Msx2), and promyelocytic leukemia zinc-finger protein (PLZF) acting upstream of Runx2, Osterix (Osx) acting downstream of Runx2, and activating transcription factor 4 (ATF4) and zinc-finger protein 521 (ZFP521) acting as cofactors of Runx2 are discussed, and their relevance for tissue engineering is presented. References are provided for more in-depth personal study.

FIG. 1.

Role of transcription factors in cell differentiation along the osteoblast and chondrocyte lineage. Runt-related transcription factor 2 (Runx2) is an essential transcription factor of early osteoblast differentiation as the master gene of bone formation. However, Runx2 is not essential for late stage of osteoblast differentiation and needs to be suppressed for terminal differentiation into osteocytes. Runx2 is also required for chondrocyte maturation.

FIG. 2.

Role and delicate regulation of Runx2 during osteoblast differentiation. Runx2 is essential for skeletal development. In osteoblast differentiation, Runx2 expression is detected in preosteoblasts expressing type I collagen weakly and is upregulated in immature osteoblasts expressing osteopontin. However, Runx2 expression is downregulated in mature osteoblasts expressing osteocalcin (OC). As the osteoblast transitions to an osteocyte expressing secreted proteins CD44, DMP1, and MEPE, alkaline phosphatase is reduced, whereas OC is elevated. The expression and transcriptional activity of Runx2 are tightly regulated by multiple proteins during osteoblast differentiation.

FIG. 3.

Runx2 as the master regulator of osteoblast differentiation is modulated by multiple transcription factors to regulate downstream factors and osteoblast differentiation. The expression and transcriptional activities of Runx2 are tightly modulated by upstream transcription factors and cofactors to regulate downstream transcription factors. As the master regulator of osteoblast differentiation, Runx2 directly binds and regulates the expression of multiple osteogenic genes that determine the osteoblast phenotype.