Dmrt2 promotes transition of endochondral bone formation by linking Sox9 and Runx2

Koichiro Ono, Kenji Hata, Eriko Nakamura, Shota Ishihara, Sachi Kobayashi, Masako Nakanishi, Michiko Yoshida, Yoshifumi Takahata, Tomohiko Murakami, Seiichi Takenoshita, Toshihisa Komori, Riko Nishimura, Toshiyuki Yoneda

Research output: Contribution to journalArticlepeer-review

Abstract

Endochondral bone formation is fundamental for skeletal development. During this process, chondrocytes undergo multiple steps of differentiation and coordinated transition from a proliferating to a hypertrophic stage, which is critical to advance skeletal development. Here, we identified the transcription factor Dmrt2 (double-sex and mab-3 related transcription factor 2) as a Sox9-inducible gene that promotes chondrocyte hypertrophy in pre-hypertrophic chondrocytes. Epigenetic analysis further demonstrated that Sox9 regulates Dmrt2 expression through an active enhancer located 18 kb upstream of the Dmrt2 gene and that this enhancer’s chromatin status is progressively activated through chondrocyte differentiation. Dmrt2-knockout mice exhibited a dwarf phenotype with delayed initiation of chondrocyte hypertrophy. Dmrt2 augmented hypertrophic chondrocyte gene expression including Ihh through physical and functional interaction with Runx2. Furthermore, Dmrt2 deficiency reduced Runx2-dependent Ihh expression. Our findings suggest that Dmrt2 is critical for sequential chondrocyte differentiation during endochondral bone formation and coordinates the transcriptional network between Sox9 and Runx2.

Original languageEnglish
Article number326
JournalCommunications Biology
Volume4
Issue number1
DOIs
Publication statusPublished - 2021 Dec
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Medicine (miscellaneous)
  • Medicine(all)

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