Transcriptional Network Controlling Endochondral Ossification

Endochondral ossification is the fundamental process of skeletal development in vertebrates. Chondrocytes undergo sequential steps of differentiation, including mesenchymal condensation, proliferation, hypertrophy, and mineralization. These steps, which are required for the morphological and functional changes in differentiating chondrocytes, are strictly regulated by a complex transcriptional network. Biochemical and mice genetic studies identified chondrogenic transcription factors critical for endochondral ossification. The transcription factor sex-determining region Y (SRY)-box 9 (Sox9) is essential for early chondrogenesis, and impaired Sox9 function causes severe chondrodysplasia in humans and mice. In addition, recent genome-wide chromatin immunoprecipitation-sequencing studies revealed the precise regulatory mechanism of Sox9 during early chondrogenesis. Runt-related transcription factor 2 promotes chondrocyte hypertrophy and terminal differentiation. Interestingly, endoplasmic reticulum (ER) stress-related transcription factors have recently emerged as novel regulators of chondrocyte differentiation. Here we review the transcriptional mechanisms that regulate endochondral ossification, with a focus on Sox9.