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. 2018 Feb 27;8:3704. doi: 10.1038/s41598-018-21735-w

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© The Author(s) 2018

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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A model for miR-214 mode of action in chondrogenesis. The levels of miR-214 during chondrogenesis are distinct in undifferentiated cells and in differentiating cells. ETS1 promotes miR-214 expression in undifferentiated cells, although other factors might impact on miR-214 expression. During differentiation, transcriptional repressors such as AP2α should overcome ETS1 action leading to the repression of miR-214 transcription and downregulate its expression. Higher levels of miR-214 contribute to maintain an undifferentiated cell state, possibly by blocking ATF4 and/or by controling Hh and WNT pathways through targeting of Sufu and β-Catenin, respectively. These actions impact on the expression of genes necessary for chondrocyte differentiation (such as SOX9 and COL2A1), which are maintained at basal levels. For chondrocyte differentiation to progress, miR-214 levels decrease thus alleviating the expression of their targets as well as the expression of chondrocyte markers. Arrows indicate activation and their relative size indicates an incremented effect. Green arrow indicates the transcriptional activation identified in this study; grey intersected line indicates transcriptional repression; red intersected lines indicate repression by miRNA; dashed black arrows indicate differentiation processes. Genes in blue letters, blue intersected lines and blue arrows represent proposed mechanisms not yet, or not completely, demonstrated.