Dupuytren's disease (DD): WNT4 knockdown in normal skin fibroblasts leads to 'DD-like' changes in the transcriptome

Abstract Introduction Dupuytren's disease (DD), a fibro-proliferative disorder of unknown aetiology, affects the palm and is characterised by progressive fibrosis, thickening of palmar fascia, and excess collagen deposition. Patients present with nodules, causing flexion deformity in ∼50%, resulting in loss of hand function. Excision is the standard treatment for DD, recurrence remains high. A 2015 Cochrane review concluded there is insufficient evidence to show superiority of any procedure used. Genetic and other studies have implicated WNT signalling in Dupuytren's pathology, including WNT4 dysregulation. It is not clear how WNT signalling/WNT4 plays a role in triggering DD. Methods Fibroblasts were isolated from the wrists of control healthy adult males and from a family that had inherited DD. Normal skin fibroblasts were treated with WNT4 siRNA and transcriptome of normal skin untreated, normal skin siRNA treated and DD family fibroblasts compared using RNASeq. Results Analysis of the transcriptomes from DD patient and normal fibroblasts showed significant differences including in WNT4 expression. Downregulation of WNT4 in normal fibroblasts using siRNA led to ‘DD-like’ changes in the transcriptome. Conclusion In people susceptible to DD WNT4 is downregulated even in non-fibrotic fibroblasts. Knockdown of WNT4 in normal fibroblasts led to changes making cells ‘DD-like’, suggesting downregulation of WNT4 could drive DD. Previous studies have shown that WNT4 is downregulated in DD disease in the cord cells. This study shows that WNT4 is downregulated in ‘non-disease’ cells, that downregulating WNT4 in normal skin fibroblasts leads to widespread ‘DD like’ changes in the transcriptome, suggesting WNT4 downregulation is a driver of DD disease.