Pathological Changes in Extracellular Matrix Composition Orchestrate the Fibrotic Feedback Loop Through Macrophage Activation in Dupuytren’s Contracture

Abstract

Dupuytren’s contracture belongs to a group of fibrotic diseases that have similar mechanisms but lack effective treatment and prevention options. The excessive accumulation of connective tissue in Dupuytren’s disease leads to palmar fibrosis that results in contracture deformities. The present study aimed to investigate how the tissue microenvironment in Dupuytren’s contracture affects the phenotypic differentiation of macrophages, which leads to an inflammatory response and the development of chronicity in fibrotic disease. We utilized a decellularization-based method combined with proteomic analysis to identify shifts in extracellular matrix composition and the surrounding tissue microenvironment. We found that the expression of several matricellular proteins, such as MFAP4, EFEMP1 (fibulin-3), and ANGPTL2, was elevated in Dupuytren’s tissue. We show that, in response to the changes in the extracellular matrix of Dupuytren’s contracture, macrophages regulate the fibrotic process by cytokine production, promote myofibroblast differentiation, and increase the fibroblast migration rate. Moreover, we found that the extracellular matrix of Dupuytren’s contracture directly supports the macrophage-to-myofibroblast transition, which could be another contributor to Dupuytren’s disease pathogenesis. Our results suggest that interactions between macrophages and the extracellular matrix should be considered as targets for novel fibrotic disease treatment and prevention strategies in the future.