Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2017.171 Figure 4 Transcriptional and epigenetic regulation of Wnt signalling in articular cartilage Figure 4 | Transcriptional and epigenetic regulation of Wnt signalling in articular cartilage. a | β-Catenin is the critical signalling molecule in the canonical Wnt signalling pathway, but is not transcriptionally active. Instead, β-catenin associates with the T cell factor (TCF) and lymphoid enhancer-binding factor (LEF) family of transcription factors. Increasing evidence suggests that deleterious activation of canonical Wnt signalling is mediated by TCF4. By contrast, binding of TCF3 and LEF1 to specific promoters could be protective. The interaction between TCF4 and β-catenin is further inhibited by hypoxia-inducible factor 1α (HIF1α). b | Enhancer of zeste homologue 2 (EZH2) and DOT1L are histone methyltransferases linked to Wnt signalling in cartilage. EZH2 increases Wnt signalling by reducing the expression of the Wnt antagonist secreted frizzled related protein 1 (sFRP1). DOT1L, part of the TCF–β-catenin complex, interacts with SIRT1 and negatively regulates Wnt signalling by inhibiting SIRT1-mediated recruitment of transcriptional activators to Wnt target genes LEF1 and TCF1. Me, methyl group; PRC2, polycomb repressive complex 2. Monteagudo, S. & Lories, R. J. (2017) Cushioning the cartilage: a canonical Wnt restricting matter Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2017.171