Fibrosis: a novel approach for an old problem

Abstract

Dupuytren’s disease is a fibroproliferative disease of the hand palm that results in permanent finger flexion and is the most common inherited condition to affect the body’s connective tissue with a global presence of 3-6%. It was originally known as the Viking’s disease and thought to be originated in the seventh or early eight century AD. In 1832 Baron Guillaume Dupuytren named and gave the first anatomo-clinical description of the disease. To date the causes underlying Dupuytren’s disease are unknown and surgery remains the standard of care. Multiple recurrences are a common feature of this disease, following surgical removal of the primary fibrotic formations. Our research focuses on understanding of the molecular mechanisms that are at the basis of the progression of fibrosis. In our recently published manuscript we described how modulation of the TGF? signaling pathway results in “reduction” of the fibrotic content of the disease. Dupuytren’s resection specimens can now be maintained ex vivo providing a suitable model for preclinical screening of different classes of potential antifibrotic drugs; antisense oligonucleotides, chemical inhibitors, and miRNA- based therapies. Our findings indicate that decrease of collagen deposition, which is pathological characteristic of Dupuytren’s, can be achieved by blocking the main regulatory pathway of collagen expression and remodeling. Short term gene expression modulation could have prolonged antifibrotic effects, even upon withdrawal of the modulatory factor (e.g. pharmacological inhibitor). Dupuytren’s field of research is shifting direction from symptom-oriented studies towards molecular pathogenesis and gene expression “correction” attempts. Future studies shall focus on the molecular, epigenetic or immune modulation of key fibrotic stimuli in combination with current treatments with ultimate goal, to not only relief the primary symptoms, but mainly to prevent recurrence of the disease. Here, we discuss the applicability of ex vivo screening of potential pre-drugs on Dupuytren’s-derived tissue for the treatment of various fibrotic diseases.