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Wnt antagonist DKK‐1 levels in systemic sclerosis are lower in skin but not blood and is regulated by microRNA33a‐3p.

Henderson, John and Pryzborski, Stefan and Stratton, Richard and O’Reilly, Steven (2020) 'Wnt antagonist DKK‐1 levels in systemic sclerosis are lower in skin but not blood and is regulated by microRNA33a‐3p.', Experimental dermatology., 30 (1). pp. 162-168.

Abstract

Background: Systemic sclerosis is an autoimmune skin disease which is associated with inflammation and resulting skin fibrosis. Myofibroblasts are the key cell type associated with the fibrosis but how they are differentiated is not clear. DKK‐1 is a Wnt antagonist that blocks Wnt‐mediated fibrosis and is reduced in fibrotic conditions. Thus DKK‐1 is a clear negative regulator of fibrosis in systemic sclerosis and its regulation is unknown.The aim of this work is to determine the levels of DKK‐1 in serum and tissues of SSc and its regulation. Methods: Skin biopsies were taken from early diffuse systemic sclerosis patients and healthy controls and DKK‐1 measured by ELISA; serum was also isolated and DKK‐1 quantified. DKK‐1 was also measured by qRT‐PCR. MicroRNA33a‐3p was measured by Taqman PCR. miR mimics and controls were transfected into dermal fibroblasts. Bleomycin mouse model was employed and compared to vehicle control treated mice and gene expression was employed for DKK‐1 and various extracellular matrix genes. Results: DKK‐1 is reduced in SSc skin and fibroblasts but is not reduced in the circulation in patients. microRNA33a‐3p regulates DKK‐1 levels epigenetically and is significantly reduced in SSc cells and whole tissue. DKK‐1 is also reduced in the bleomycin mouse modelandpro‐fibrotic genes elevated. Conclusion: DKK‐1 is reduced in SSc cells and is regulated by miR33a‐3p and restoring DKK‐1 levels through epigenetic means could be a therapeutic target in systemic sclerosis.

Item Type:Article
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Status:Peer-reviewed
Publisher Web site:https://doi.org/10.1111/exd.14136
Publisher statement:© 2020 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Date accepted:22 June 2020
Date deposited:16 September 2020
Date of first online publication:10 September 2020
Date first made open access:16 September 2020

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