Sustained ß-catenin activity in dermal fibroblasts promotes fibrosis by up-regulating expression of extracellular matrix protein-coding genes.

ABSTRACT

Fibrosis is an end-stage response to tissue injury that is associated with loss of organ function as a result of excess extracellular matrix (ECM) production by fibroblasts. In skin, pathological fibrosis is evident during keloid scar formation, systemic sclerosis (SSc) and morphea. Dermal fibroblasts in these fibrotic diseases exhibit increased Wnt/ß-catenin signalling, a pathway that is sufficient to cause fibrosis in mice. However, in the context of this complex pathology, the precise pro-fibrotic consequences of Wnt/ß-catenin signalling are not known. We found that expression of stabilized ß-catenin in mouse dermal fibroblasts resulted in spontaneous, progressive skin fibrosis with thickened collagen fibres and altered collagen fibril morphology. The fibrotic phenotype was predominated by resident dermal fibroblasts. Genome-wide profiling of the fibrotic mouse dermis revealed elevated expression of matrix-encoding genes, and the promoter regions of these genes were enriched for Tcf/Lef family transcription factor binding sites. Additionally, we identified 32 ß-catenin-responsive genes in our mouse model that are also over-expressed in human fibrotic tissues and poised for regulation by Tcf/Lef family transcription factors. Therefore, we have uncovered a matrix-regulatory role for stabilized ß-catenin in fibroblasts in vivo and have defined a set of ß-catenin-responsive genes with relevance to fibrotic disease.