hypoxia inhibits osteogenesis in human mesenchymal stem cells through direct regulation of runx2 by twist缺氧抑制骨在人类间充质干细胞通过直接调节runx2的转折.pdfVIP

Hypoxia Inhibits Osteogenesis in Human Mesenchymal Stem Cells through Direct Regulation of RUNX2 by TWIST 1,5 1,7. 2,5. 3,6,7 4 Der-Chih Yang , Muh-Hwa Yang , Chih-Chien Tsai , Tung-Fu Huang , Yau-Hung Chen *, Shih- Chieh Hung1,2,5,6* 1 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, 2 Pharmacology, National Yang-Ming University, Taipei, Taiwan, 3 Department of Surgery, National Yang-Ming University, Taipei, Taiwan, 4 Department of Chemistry, Tamkang University, Taipei, Taiwan, 5 Department of Medical Research and Education, Veterans General Hospital-Taipei, Taipei, Taiwan, 6 Orthopaedics and Traumatology, Veterans General Hospital-Taipei, Taipei, Taiwan, 7 Hematology-Oncology, Veterans General Hospital-Taipei, Taipei, Taiwan Abstract Background: Bone loss induced by hypoxia is associated with various pathophysiological conditions, however, little is known about the effects of hypoxia and related signaling pathways on osteoblast differentiation and bone formation. Because bone marrow-derived mesenchymal stem cells (MSCs) survive under hypoxic conditions and readily differentiate into osteoblasts by standard induction protocols, they are a good in vitro model to study the effects of hypoxia on osteoblast differentiation. Methodology/Principle Findings: Using human MSCs, we discovered TWIST, a downstream target of HIF-1a, was induced under hypoxia and acted as a transcription repressor of RUNX2 through binding to the E-box located on the promoter of type 1 RUNX2. Suppression of type 1 RUNX2 by TWIST under hypoxia further inhibited the expression of BMP2, type 2 RUNX2 and downstream targets of RUNX