Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms.
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| Abstract |
Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB)-a severe skin fragility disorder associated with lifelong blistering and disabling progressive soft tissue fibrosis. Causative therapies for this complex disorder face major hurdles, and clinical implementation remains elusive. Here, we report an alternative evidence-based approach to ameliorate fibrosis and relieve symptoms in RDEB. Based on the findings that TGF-β activity is elevated in injured RDEB skin, we targeted TGF-β activity with losartan in a preclinical setting. Long-term treatment of RDEB mice efficiently reduced TGF-β signaling in chronically injured forepaws and halted fibrosis and subsequent fusion of the digits. In addition, proteomics analysis of losartan- vs. vehicle-treated RDEB skin uncovered changes in multiple proteins related to tissue inflammation. In line with this, losartan reduced inflammation and diminished TNF-α and IL-6 expression in injured forepaws. Collectively, the data argue that RDEB fibrosis is a consequence of a cascade encompassing tissue damage, TGF-β-mediated inflammation, and matrix remodeling. Inhibition of TGF-β activity limits these unwanted outcomes and thereby substantially ameliorates long-term symptoms.
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| Authors | Alexander Nyström, Kerstin Thriene, Venugopal Mittapalli, Johannes S Kern, Dimitra Kiritsi, Jörn Dengjel, Leena Bruckner-Tuderman |
| Journal | EMBO molecular medicine (EMBO Mol Med) Vol. 7 Issue 9 Pg. 1211-28 (Sep 2015) ISSN: 1757-4684 [Electronic] England |
| PMID | 26194911 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | © 2015 The Authors. Published under the terms of the CC BY 4.0 license. |
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