S100A4 is a high glucose-induced fibrotic factor in Dupuytren’s contracture

Dupuytren’s contracture is a superficial fibrotic disease of the hand, which causes flexion contracture of the affected finger. Among several risk factors for Dupuytren’s contracture, diabetes mellitus (DM) is a well-known risk factor for this disease. While epidemiological studies demonstrated a high prevalence of DM in patients with Dupuyren’s contractures, the exact underlying mechanism by which DM is involved in their development and progression are still unknown. Here, we investigate how glycometabolic disorder is involved in the pathogenesis of Dupuytren’s contracture. RNA sequencing reveal that Dupuytren’s contracture-derived fibroblasts treated with high-glucose media upregulated S100A4 (also called fibroblast-specific protein, Fsp1) expression compared to those with low-glucose media. The expression of S100A4 in Dupuytren’s contracture tissues is significantly increased in diabetic patients than in nondiabetic patients. S100A4 is expressed by several types of cells, including fibroblast, myofibroblast and macrophages, however expression of its receptor, Toll-like receptor 4 (TLF4), is observed predominantly in CD68-expressing macrophages. Furthermore, S100A4 treatment significantly increases TGF-β1 expression in macrophages, and pharmacological inhibition of TLR4 decreases TGF-β1. Thus, the S100A4–TLR4–TGF-β axis could be a potential therapeutic target for Dupuytren’s contracture occurring in the diabetic hand.