Hypoxia-Inducible Factor 1 Is an Inductor of Transcription Factor Activating Protein 2 Epsilon Expression during Chondrogenic Differentiation

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Abstract
The transcription factor AP-2ε(activating enhancer-binding protein epsilon) is expressed in cartilage of humans and mice. However, knowledge about regulatory mechanisms influencing AP-2εexpression is limited. Using quantitative real time PCR, we detected a significant increase in AP-2εmRNA expression comparing initial and late stages of chondrogenic differentiation processesin vitroandin vivo. Interestingly, in these samples the expression pattern of the prominent hypoxia marker geneangiopoietin-like 4 (Angptl4)strongly correlated with that ofAP-2εsuggesting that hypoxia might represent an external regulator of AP-2εexpression in mammals. In order to show this, experiments directly targeting the activity of hypoxia-inducible factor-1 (HIF1), the complex mediating responses to oxygen deprivation, were performed. While the HIF1-activating compounds 2,2′-dipyridyl and desferrioxamine resulted in significantly enhanced mRNA concentration of AP-2ε, siRNA against HIF1αled to a significantly reduced expression rate ofAP-2ε. Additionally, we detected a significant upregulation of the AP-2εmRNA level after oxygen deprivation. In sum, these different experimental approaches revealed a novel role for the HIF1 complex in the regulation of theAP-2εgene in cartilaginous cells and underlined the important role of hypoxia as an important external regulatory stimulus during chondrogenic differentiation modulating the expression of downstream transcription factors.
Funding Information
  • Deutsche Forschungsgemeinschaft

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