TCF4 is a pro-catabolic and apoptotic factor in human articular chondrocytes by potentiating NF-κB signaling

Bin Ma, Leilei Zhong, Clemens van Blitterswijk, Janine Nicole Post, Hermanus Bernardus Johannes Karperien

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Abstract

TCF/LEF transcription factors are downstream mediators of Wnt/β-catenin signaling which has been implicated in the development and progression of osteoarthritis (OA). This study aimed to investigate the role of TCF/LEF transcription factors in human articular chondrocytes. Primary human osteoarthritic cartilage predominantly expressed TCF4 and to a lesser extent, LEF1 and TCF3 mRNA. Overexpression of TCF4, but not of TCF3 or LEF1, induced MMP-1, -3, and -13 expression and generic MMP activity in human chondrocytes This was due to potentiating NF-κB signaling by a protein-protein interaction between TCF4 and NF-κB p65 activating established NF-κB target genes such as MMPs and IL6. LEF1 competed with TCF4 for binding to NF-κB p65. IκB-α was able to counteract the effect of TCF4 on NF-κB target gene expression. Finally we showed that TCF4 mRNA expression was elevated in OA cartilage compared to healthy cartilage and induced chondrocyte apoptosis at least partly through activating caspase 3/7. Our findings suggest that increased TCF4 expression may contribute to cartilage degeneration in OA by augmenting NF-κB signaling.
Original languageEnglish
Pages (from-to)17552-17558
JournalJournal of biological chemistry
Volume288
DOIs
Publication statusPublished - 19 Apr 2013

Keywords

  • METIS-295851
  • IR-85519

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