J Bone Metab.  2017 May;24(2):75-82. 10.11005/jbm.2017.24.2.75.

Transcriptional Network Controlling Endochondral Ossification

• Hata K
• Takahata Y
• Murakami T
• Nishimura

• KMID: 2379988
• DOI: http://doi.org/10.11005/jbm.2017.24.2.75

Abstract

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.

Keyword

Chondrocytes; Osteogenesis; SOX9 transcription factor; Transcription factors

MeSH Terms

Animals
Chondrocytes
Chondrogenesis
Chromatin
Endoplasmic Reticulum
Gene Regulatory Networks*
Humans
Hypertrophy
Mice
Miners
Osteogenesis
SOX9 Transcription Factor
Transcription Factors
Vertebrates
Chromatin
SOX9 Transcription Factor
Transcription Factors

Figure

• 

  Fig. 1 Schematic representation of chondrocyte differentiation steps during endochondral ossification. Endochondral ossification starts with mesenchymal condensation followed by the sequential differentiation steps indicated in the figure. Stage-specific marker genes and essential transcription factors are shown. Col, collagen; Sox9, sex-determining region Y-box 9; Runx2, runt-related transcription factor 2; Ihh, indian hedgehog; Mmp13, matrix metalloproteinase 13.

• 

  Fig. 2 Schematic representation of sex-determining region Y-box 9 (Sox9) and its coactivators in chondrocyte differentiation. Sox9 directly binds to the collagen type II α 1 chain (Col2a1) enhancer region along with various transcriptional coactivators to construct a large transcriptional complex. Each coactivator regulates different steps of transcription, including histone demethylation, histone acetylation, and RNA splicing, to promote chondrocyte gene expression. Arid5a, AT-rich interactive domain 5A; Arid5b, AT-rich interactive domain 5B; wwp2, WW domain containing E3 ubiquitin protein ligase 2; Znf219, zinc finger protein 219; Tip60, Tat interactive protein-60.

• 

  Fig. 3 Working model of BBF2 human homolog on chromosome 7 (BBF2H7) during chondrocyte differentiation. Full-length BBF2H7 is normally located in the endoplasmic reticulum (ER) membrane of chondrocytes. In response to ER stress, BBF2H7 is cleaved by regulated intramembrane proteolysis (RIP) and the cleaved N-terminal cytoplasmic domain of BBF2H7 translocates into the nucleus, which induces the transcription of the ER–Golgi trafficking protein Sec23 homolog A, coat complex II component (Sec23a). CRE, cAMP response element; ECM, extracellular matrix.

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