Unraveling the signaling pathways promoting fibrosis in Dupuytren's disease reveals TNF as a therapeutic target

Abstract

Significance Fibrosis, a hallmark of many clinical disorders, occurs because of uncontrolled myofibroblast activity. We studied Dupuytren's disease, a common hereditable fibrotic condition that causes the fingers to irreversibly curl toward the palm. We found that freshly isolated tissue from Dupuytren's patients contained macrophages and released proinflammatory protein mediators (cytokines). Of the cytokines, only TNF selectively converted normal fibroblasts from the palm of patients with Dupuytren's disease into myofibroblasts via activation of the Wnt signaling pathway. Conversely, blockade of TNF resulted in reversal of the myofibroblast phenotype. Therefore, TNF inhibition may prevent progression or recurrence of Dupuytren's disease.

SNPs Previously Associated with Dupuytren's Disease Replicated in a North American Cohort

“…33,34 Our study supports the findings of the Dolmans et al study. 22 Larger consortium studies can utilize these results to develop risk stratification and, potentially, novel detection methods and treatments for DD.…”

Compromised peroxisomes in idiopathic pulmonary fibrosis, a vicious cycle inducing a higher fibrotic response via TGF-β signaling

“…It is known that TNF-α −/− mice develop less liver fibrosis in comparison with littermate controls, exhibit reduced levels of α-SMA, a marker for activated myofibroblasts, and reduced TGF-β1 mRNA (19). Consistent with our findings are the existing evidences from the literature that TNF-α is crucial in initiation and progression of the fibrotic processes via AP-1 in Swiss 3T3 fibroblasts (7,20). Similarly, the interplay between Smad-dependent TGF-β signaling and AP-1 that we observed in our study has also been reported in numerous studies and are contradicting.…”

Strategies to overcome the hurdles to treat fibrosis, a major unmet clinical need

“…Neutralization of secreted factors is easier than intracellular pathways or particular cell types. Study of diseased and appropriate control human tissues resulted in the identification of TNF as a therapeutic target for Dupuytren's disease (22), and a phase II clinical trial is in progress (23).…”