title: T cell factor 4 is a pro-catabolic and apoptotic factor in human articular chondrocytes by potentiating nuclear factor κB signaling.
abstract: T cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors are downstream effectors 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 IL-6. 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 with 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.
authors.affiliation: Department of Developmental BioEngineering, University of Twente, Enschede 7522NB, The Netherlands.
authors.forename: Bin
authors.initials: B
authors.lastname: Ma
authors.forename: Leilei
authors.initials: L
authors.lastname: Zhong
authors.forename: Clemens A
authors.initials: CA
authors.lastname: van Blitterswijk
authors.forename: Janine N
authors.initials: JN
authors.lastname: Post
authors.forename: Marcel
authors.initials: M
authors.lastname: Karperien
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D002358:Cartilage, Articular / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D053505:Matrix Metalloproteinases, Secreted / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D020370:Osteoarthritis, Knee / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058118:Transcription Factor 7-Like 2 Protein / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D016328:NF-kappa B; C498143:RELA protein, human; D012333:RNA, Messenger; D058118:Transcription Factor 7-Like 2 Protein; D051996:Transcription Factor RelA; D053505:Matrix Metalloproteinases, Secreted
keywords: Apoptosis; Chondrocytes; Matrix Metalloproteinase (MMP); NF-κB; T Cell Factor (TCF)