S100A4–TLR4–TGF-β axis as a therapeutic target for Dupuytren’s contracture in diabetic patients

Dupuytren's contracture is a superficial fibrotic disease of the hands that causes flexion contractures of the affected fingers. Diabetes mellitus (DM) is a risk factor for Dupuytren's contracture. However, the exact underlying mechanisms by which DM is involved in its development and progression remain unknown. This study investigated the involvement of glycometabolic disorders in the pathogenesis of Dupuytren's contracture. RNA sequencing revealed that S100A4 expression was significantly increased in Dupuytren's contracture-derived fibroblasts under high-glucose conditions compared with low-glucose conditions, and this finding was confirmed by immunoblotting and enzyme-linked immunosorbent assay. S100A4 expression in Dupuytren's contracture tissues was significantly higher in patients with diabetes than in those without. S100A4 was expressed in several cell types, including fibroblasts, myofibroblasts, and macrophages. However, the expression of its receptor, Toll-like receptor 4 (TLR4), was predominantly detected in CD68-expressing macrophages. Furthermore, recombinant S100A4 treatment significantly increased transforming growth factor-beta 1 (TGF-β1) expression, which is a central mediator of fibrosis, in macrophages. Pharmacological inhibition of TLR4 suppresses TGF-β1 upregulation via S100A4. Thus, the S100A4-TLR4-TGF-β axis could be a potential therapeutic target for Dupuytren's contracture in diabetic patients.