| First Author | Nyström A | Year | 2015 |
| Journal | EMBO Mol Med | Volume | 7 |
| Issue | 9 | Pages | 1211-28 |
| PubMed ID | 26194911 | Mgi Jnum | J:233535 |
| Mgi Id | MGI:5784942 | Doi | 10.15252/emmm.201505061 |
| Citation | Nystrom A, et al. (2015) Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms. EMBO Mol Med 7(9):1211-28 |
| abstractText | 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-beta activity is elevated in injured RDEB skin, we targeted TGF-beta activity with losartan in a preclinical setting. Long-term treatment of RDEB mice efficiently reduced TGF-beta 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-alpha and IL-6 expression in injured forepaws. Collectively, the data argue that RDEB fibrosis is a consequence of a cascade encompassing tissue damage, TGF-beta-mediated inflammation, and matrix remodeling. Inhibition of TGF-beta activity limits these unwanted outcomes and thereby substantially ameliorates long-term symptoms. |
