T Cell Factor 4 Is a Pro-catabolic and Apoptotic Factor in Human Articular Chondrocytes by Potentiating Nuclear Factor κB Signaling*

Background: TCF/LEF transcription factors are downstream effectors of Wnt/β-catenin signaling. Results: TCF4 stimulates MMP expression and apoptosis in human articular chondrocytes by potentiating NF-κB signaling. Conclusion: Increased TCF4 expression may contribute to cartilage degeneration in osteoarthritis. Significance: Study of Wnt signaling transcription factors opens a new window for the treatment of degenerative cartilage disease. 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.