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

• DOI: 10.1073/pnas.1301100110
• Publication Date: 2013-02-20T06:56:59Z
• Authors: Liaquat S. Verjee; Jennifer S. N. Ve...; James K. K. Chan; Thomas Krausgruber; Vicky Nicolaidou; David Izadi; Dominique Davidson; Marc Feldmann; Kim S. Midwood; Jagdeep Nanchahal
• Keywords: 0303 health sciences; Glycogen Synthase Kinase 3 beta; Tumor Necrosis Factor-alpha; Macrophage Activation; Fibrosis; Models, Biological; Recombinant Proteins; 3. Good health; Dupuytren Contracture; Transforming Growth Factor beta1; Glycogen Synthase Kinase 3; 03 medical and health sciences; Phenotype; Disease Progression; Cytokines; Humans; Myofibroblasts; Wnt Signaling Pathway; Cells, Cultured

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.