Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, Korea Mouse Phenotyping Center, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
Department of Food and Nutrition, Human Ecology Research Institute, Chonnam National University, Gwangju, Republic of Korea.
J Cell Physiol. 2021 Oct;236(10):6963-6973. doi: 10.1002/jcp.30356. Epub 2021 Mar 21.
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.
缺氧环境对于软骨细胞的成熟和长骨生长至关重要。虽然缺氧诱导因子 1 ɑ（Hif-1ɑ）已被认为是软骨细胞存活和功能的关键因子，但 Hif-2ɑ在软骨中的功能在机制和临床上都具有相关性，但目前尚不清楚。在这里，我们通过下调 Runx2 的稳定性，证明 Hif-2ɑ是一种新型的软骨细胞成熟抑制剂。在机制上，Hif-2ɑ通过破坏 Runx2/Cbfβ 复合物的形成，与 Runx2 结合抑制软骨细胞成熟，从而导致 Runx2 的降解。由于增加了 Runx2/Cbfβ 复合物的形成，Cbfβ 的转染可以挽救 Hif-2α 介导的 Runx2 降解。同样，在微团培养系统中，Hif-2ɑ杂合子小鼠来源的间充质细胞比野生型小鼠更快地分化为肥大软骨细胞。综上所述，这些发现表明，Hif-2ɑ通过破坏 Runx2/Cbfβ 复合物的形成和随后的调节活性，成为一种新型的软骨细胞成熟抑制剂。
