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Diversity of Mechanisms Underlying Latent TGF-β Activation in Recessive Dystrophic Epidermolysis Bullosa.

Authors
  • Akasaka, Eijiro1
  • Kleiser, Svenja2
  • Sengle, Gerhard3
  • Bruckner-Tuderman, Leena1
  • Nyström, Alexander4
  • 1 Department of Dermatology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany. , (Germany)
  • 2 Department of Dermatology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany. , (Germany)
  • 3 Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany; Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cologne Center for Musculoskeletal Biomechanics (CCMB), Cologne, Germany. , (Germany)
  • 4 Department of Dermatology, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany. Electronic address: [email protected] , (Germany)
Type
Published Article
Journal
Journal of Investigative Dermatology
Publisher
Elsevier
Publication Date
Jun 01, 2021
Volume
141
Issue
6
Identifiers
DOI: 10.1016/j.jid.2020.10.024
PMID: 33333127
Source
Medline
Language
English
License
Unknown

Abstract

Injury- and inflammation-driven progressive dermal fibrosis is a severe manifestation of recessive dystrophic epidermolysis bullosa-a genetic skin blistering disease caused by mutations in COL7A1. TGF-β activation plays a prominent part in progressing dermal fibrosis. However, the underlying mechanisms are not fully elucidated. TGF-β is secreted in a latent form, which has to be activated for its biological functions. In this study, we determined that recessive dystrophic epidermolysis bullosa fibroblasts have an enhanced capacity to activate the latent form. Mechanistic and functional assessment demonstrated that this process depends on multiple latent TGF-β activators, including TSP-1, RGD-binding integrins, matrix metalloproteinases, and ROS, which act in concert, in a self-perpetuating feedback loop to progress fibrosis. Importantly, our study also disclosed keratinocytes as prominent facilitators of fibrosis in recessive dystrophic epidermolysis bullosa. They stimulate microenvironmental latent TGF-β activation through enhanced production of the above mediators. Collectively, our study provides data on the molecular mechanism behind dysregulated TGF-β signaling in recessive dystrophic epidermolysis bullosa, which are much needed for the development of evidence-based fibrosis-delaying treatments. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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