title: Hypoxia inhibits osteogenesis in human mesenchymal stem cells through direct regulation of RUNX2 by TWIST.
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.
  
  
  RESULTS
  Using human MSCs, we discovered TWIST, a downstream target of HIF-1α, 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 RUNX2 in MSCs.
  
  
  CONCLUSIONS
  Our findings point to the important role of hypoxia-mediated signalling in osteogenic differentiation in MSCs through direct regulation of RUNX2 by TWIST, and provide a method for modifying MSC osteogenesis upon application of these cells in fracture healing and bone reconstruction.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Der-Chih
authors.initials: DC
authors.lastname: Yang
authors.forename: Muh-Hwa
authors.initials: MH
authors.lastname: Yang
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Tsai
authors.forename: Tung-Fu
authors.initials: TF
authors.lastname: Huang
authors.forename: Yau-Hung
authors.initials: YH
authors.lastname: Chen
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Hung
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D051879:Twist-Related Protein 1 / Q000378:metabolism*
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051879:Twist-Related Protein 1