Sustained AWT1 expression by Dupuytren's disease myofibroblasts promotes a proinflammatory milieu

Palmar fibromatosis, also known as Dupuytren's disease (DD), is a common and heritable fibrosis of the hand. It is characterized by the formation of myofibroblastic nodules that can progress to palmar-digital contractures and permanent loss of dexterity. The presence of inflammatory cell infiltrate within these nodules has been interpreted to suggest a pathogenesis mediated by a proinflammatory microenvironment. However, the molecular mechanisms driving the formation of pro-fibrotic microenvironments in this and other fibroses remain unclear. To gain insights into this process, we have assessed the contributions of an alternatively spliced, multi-functional transcription factor, Wilms Tumor 1 (WT1), previously shown to be upregulated in primary myofibroblasts derived from DD tissues. Proinflammatory cytokine stimuli of DD myofibroblasts enhanced the expression of several distinct WT1 variants, the most sustained being a 5' truncated version of WT1, alternative WT1 (AWT1). Constitutive adenoviral expression of AWT1 in myofibroblasts derived from phenotypically non-fibrotic palmar fascia significantly induced the expression and secretion of proinflammatory cytokines, including some with potential as novel therapeutic targets. In summary, these data implicate roles for sustained AWT1 expression in DD as a transcriptional driver of a proinflammatory fascial milieu.