Hypoxia-inducible factor 2α is a novel inhibitor of chondrocyte maturation

Xiangguo Che, Na Rae Park, Xian Jin, Youn Kwan Jung, Min Su Han, Clara Yongjoo Park, Jang Soo Chun, Seong Gon Kim, Jingchun Jin, Hyun Ju Kim, Jane B. Lian, Janet L. Stein, Gary S. Stein, Je Yong Choi

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Hypoxic environment is essential for chondrocyte maturation and longitudinal bone growth. Although hypoxia-inducible factor 1 alpha (Hif-1α) has been known as a key player for chondrocyte survival and function, the function of Hif-2α in cartilage is mechanistically and clinically relevant but remains unknown. Here we demonstrated that Hif-2α was a novel inhibitor of chondrocyte maturation through downregulation of Runx2 stability. Mechanistically, Hif-2α binding to Runx2 inhibited chondrocyte maturation by Runx2 degradation through disrupting Runx2/Cbfβ complex formation. The Hif-2α-mediated-Runx2 degradation could be rescued by Cbfβ transfection due to the increase of Runx2/Cbfβ complex formation. Consistently, mesenchymal cells derived from Hif-2α heterozygous mice were more rapidly differentiated into hypertrophic chondrocytes than those of wild-type mice in a micromass culture system. Collectively, these findings demonstrate that Hif-2α is a novel inhibitor for chondrocyte maturation by disrupting Runx2/Cbfβ complex formation and consequential regulatory activity.

Original languageEnglish
Pages (from-to)6963-6973
Number of pages11
JournalJournal of Cellular Physiology
Volume236
Issue number10
DOIs
StatePublished - Oct 2021

Keywords

  • Cbfβ
  • chondrocyte maturation
  • Hif-2α
  • Proteasomal degradation
  • Runx2

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