Uncoupling TGFβ1 signalling from collagen protein synthesis in Dupuytren's disease.

Dupuytren's disease is a fibroproliferative disorder of the palmer fascia (PF) characterised by flexion contractures in the hand. Dupuytren's disease can be treated surgically, but disease recurrence rates are high, potentially due to continual production of matrisomal proteins. Here, metabolic labelling and proteomics identified differences in the new synthesis and composition of matrisomal proteins between Dupuytren's tissue and normal PF. Dupuytren's tissue actively synthesised type I collagen, fibronectin (FN1), matrix metalloproteinases-2 and -3 (MMP2, MMP3) and tissue inhibitor of metalloproteinases 2 (TIMP2). Both tissues actively synthesised insulin-like growth factor binding protein 7 (IGFBP7). Label-free analysis implicated the transforming growth factor-β (TGFβ) pathway in the matrisomal profile of Dupuytren's tissue. The effect of TGFβ isoforms on COL1 mRNA expression was first tested in cultured young and aged equine tenocytes. COL1A1 mRNA responded to treatment with all TGFβ isoforms and was more highly expressed in cells from aged samples. In aged human cells, COL1A1 and COL1A2 mRNA was higher in cells derived from Dupuytren's tissue than normal PF and in response to TGFβ1, but no changes in COL1A1 or COL1A2 CpG methylation were detected. TGFβ1 treatment only resulted in increased type I collagen protein accumulation in the media of Dupuytren's nodule cells. In three-dimensional cultures, COL1A1 mRNA was lower in normal PF than in Dupuytren's cells, but TGFβ1 treatment only increased type I collagen accumulation in the media of normal PF cultures, and TGFβ1 inhibition did not alter new collagen protein synthesis. TGFβ1 inhibition in Dupuytren's tissue explants did not alter the proportion of homotrimeric type I collagen, nor was this changed in skin or tendon of the tight-skin (TSK) mouse, a naturally occurring model of indirect TGFβ1 activation. Therefore, the role of TGFβ in Dupuytren's disease may be predominantly related to myofibroblast phenoconversion and contractility rather than directly altering collagen protein synthesis. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.