The cartilage‐specific transcription factor Sox9 regulates AP‐2ε expression in chondrocytes

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Abstract
Activating enhancer‐binding protein (AP)‐2ε was previously described as a new regulator of integrin α10 expression in cartilage. In this study, we analyzed the expression of AP‐2ε in differentiated chondrocytes and in human mesenchymal stem cells (HMSCs), which have been differentiated into chondrocytes in vitro. AP‐2ε is predominantly expressed during the late stages of chondrocyte differentiation, mainly in early hypertrophic cartilage, consistent with immunohistochemical stainings of mouse embryo sections. Furthermore, osteoarthritic chondrocytes, resembling a hypertrophic phenotype, have high AP‐2ε levels. The AP‐2ε promoter harbors binding sites for the transcription factors AP‐2α and Sox9. Both transcription factors strongly activate AP‐2ε expression in a cooperative manner in the chondrosarcoma cell line SW1353. The inhibition of Sox9 expression by small interfering RNA resulted in decreased AP‐2ε expression. In addition, direct interaction of Sox9 with the AP‐2ε promoter could be confirmed by chromatin immunoprecipitation and electromobility shift assays. This is the first study to prove the direct regulation of AP‐2ε by the transcription factor Sox9, and to indicate that AP‐2ε potentially has an important role as a modulator of hypertrophic cartilage.

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