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Function-Blocking RHAMM Peptides Attenuate Fibrosis and Promote Antifibrotic Adipokines in a Bleomycin-Induced Murine Model of Systemic Sclerosis.

Authors
  • Wu, Kitty Yuechuan1
  • Kim, Stephanie2
  • Liu, Violet Muhan3
  • Sabino, Alexis4
  • Minkhorst, Kathryn5
  • Yazdani, Arjang1
  • Turley, Eva A6
  • 1 Division of Plastic and Reconstructive Surgery, Western University, London, Ontario, Canada. , (Canada)
  • 2 Division of Plastic and Reconstructive Surgery, Western University, London, Ontario, Canada; Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. , (Canada)
  • 3 Department of Biochemistry, Western University, London, Ontario, Canada. , (Canada)
  • 4 Department of Life Sciences, Queen's University, Kingston, Ontario, Canada. , (Canada)
  • 5 Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada. , (Canada)
  • 6 London Regional Cancer Program, London Health Sciences Centre, London, Ontario, Canada. Electronic address: [email protected] , (Canada)
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.2019.11.032
PMID: 33242499
Source
Medline
Language
English
License
Unknown

Abstract

Systemic sclerosis a chronic, fibrotic disorder associated with high disease-specific mortality and morbidity. Cutaneous manifestations include dermal thickening and obliteration of dermal adipose tissue. Accumulation of low-molecular-weight hyaluronan, which signals through the receptor for hyaluronan-mediated motility, RHAMM, leads to progressive fibrosis and is correlated with increased severity of systemic sclerosis. The purpose of this study is to test the efficacy of two function-blocking RHAMM peptides, NPI-110 and NPI-106, in reducing skin fibrosis in a bleomycin-induced mouse model of systemic sclerosis. NPI-110 reduced visible measures of fibrosis (dermal thickness and collagen production, deposition, and organization) and profibrotic gene expression (Tgfb1, c-Myc, Col1a1, Col3a1). NPI-110 treatment also increased the expression of the antifibrotic adipokines perilipin and adiponectin. Both RHAMM peptides strongly reduced dermal RHAMM expression, predicting that dermal fibroblasts are peptide targets. Transcriptome and cell culture analyses using Rhamm-/- and Rhamm-rescued dermal fibroblasts reveal a TGFβ1/RHAMM/MYC signaling axis that promotes fibrogenic gene expression and myofibroblast differentiation. RHAMM function‒blocking peptides suppress this signaling and prevent TGFβ1-induced myofibroblast differentiation. These results suggest that inhibiting RHAMM signaling will offer a treatment method for cutaneous fibrosis in systemic sclerosis. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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