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

Research output: Contribution to journalArticleAcademicpeer-review

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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

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TCF Transcription Factors
Cartilage
Chondrocytes
Joints
Matrix Metalloproteinases
Osteoarthritis
Caspase 7
Catenins
Messenger RNA
Gene expression
Human Activities
Caspase 3
Interleukin-6
Proteins
Genes
Apoptosis
Gene Expression

Keywords

  • METIS-295851
  • IR-85519

Cite this

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title = "TCF4 is a pro-catabolic and apoptotic factor in human articular chondrocytes by potentiating NF-κB signaling",
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.",
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TCF4 is a pro-catabolic and apoptotic factor in human articular chondrocytes by potentiating NF-κB signaling. / Ma, Bin; Zhong, Leilei; van Blitterswijk, Clemens; Post, Janine Nicole; Karperien, Hermanus Bernardus Johannes.

In: Journal of biological chemistry, Vol. 288, 19.04.2013, p. 17552-17558.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - TCF4 is a pro-catabolic and apoptotic factor in human articular chondrocytes by potentiating NF-κB signaling

AU - Ma, Bin

AU - Zhong, Leilei

AU - van Blitterswijk, Clemens

AU - Post, Janine Nicole

AU - Karperien, Hermanus Bernardus Johannes

N1 - Article in press

PY - 2013/4/19

Y1 - 2013/4/19

N2 - 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.

AB - 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.

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