Research ArticlePhysiology

Oxidative DNA damage induces the ATM-mediated transcriptional suppression of the Wnt inhibitor WIF-1 in systemic sclerosis and fibrosis

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Science Signaling  02 Sep 2014:
Vol. 7, Issue 341, pp. ra84
DOI: 10.1126/scisignal.2004592

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Connecting DNA Damage to Fibrotic Skin Thickening

Systemic sclerosis (SSc) is an autoimmune disease characterized by the accumulation of collagen in the connective tissue, a process known as fibrosis. Fibrosis affects skin and internal organs and is frequently associated with activation of the Wnt signaling pathway. Svegliati et al. found loss of the Wnt inhibitor WIF-1 in skin biopsies from SSc patients compared with healthy skin. Antibodies in serum from SSc patients or oxidative DNA-damaging agents triggered a transcriptional suppression pathway that suppressed WIF-1 expression and promoted collagen production in normal fibroblasts. In fibroblasts cultured from SSc patients, inhibiting this pathway restored WIF-1 expression and reduced collagen production; in a mouse model of fibrosis, inhibiting this pathway prevented fibrotic skin thickening.

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