John Henderson
microRNA27a-3p mediates reduction of the Wnt antagonist sFRP-1 in systemic sclerosis
Henderson, John; Wilkinson, Sarah; Przyborski, Stefan; Stratton, Richard; O’Reilly, Steven
Authors
Sarah Wilkinson
Professor Stefan Przyborski stefan.przyborski@durham.ac.uk
Deputy Provost
Richard Stratton
Steven O’Reilly
Abstract
Systemic Sclerosis (SSc) is an autoimmune connective tissue disease that leads to skin and lung fibrosis. The Wnt pathway is clearly elevated in SSc and is pro-fibrotic via activation of canonical Wnt signalling. sFRP-1 is a Wnt antagonist that acts as a negative regulator of Wnt signalling. We sought to measure the levels of serum sFRP-1 in early diffuse SSc patients compared to healthy controls and if this is regulated by microRNA27a-3p. Ten early diffuse SSc patients and healthy controls sera were taken and sFRP-1 quantified by ELISA. Skin biopsies were also taken in five SSc patients and controls. Fibroblasts were quantified for microRNA27-3p expression by Taqman qRT-PCR with an internal microRNA to normalize. 3ʹUTR luciferase assays were performed to confirm direct targets of microRNA27a-3p with microRNA overexpression. Fibroblasts were transfected with microRNA27a mimics or scramble controls and using ELISA sFRP-1 was quantified. Furthermore, Collagen, Axin-2, TIMP-1 and MMP-1 were measured. Serum sFRP-1 was significantly reduced in early diffuse SSc patients. We identified microRNA27a-3p-3p as regulating sFRP-1 in dermal fibroblasts. We found significantly elevated microRNA27a-3p in isolated dermal fibroblasts from SSc patients. We confirmed that sFRP-1 is a direct target of microRNA27a-3p through cloning of the 3ʹUTR into a luciferase vector. ECM genes were also upregulated by microRNA27a-3p-3p and the matrix-degrading enzyme MMP-1 was suppressed. Serum sFRP-1 is reduced in diffuse SSc patients and is regulated by microRNA27a-3p and this is a direct regulation. Modulation of microRNA27a-3p levels could mediate fibrosis regression.
Citation
Henderson, J., Wilkinson, S., Przyborski, S., Stratton, R., & O’Reilly, S. (2021). microRNA27a-3p mediates reduction of the Wnt antagonist sFRP-1 in systemic sclerosis. Epigenetics, 16(7), 808-817. https://doi.org/10.1080/15592294.2020.1827715
Journal Article Type | Article |
---|---|
Acceptance Date | Aug 18, 2020 |
Online Publication Date | Oct 4, 2020 |
Publication Date | 2021 |
Deposit Date | Oct 30, 2020 |
Publicly Available Date | Oct 4, 2021 |
Journal | Epigenetics |
Print ISSN | 1559-2294 |
Electronic ISSN | 1559-2308 |
Publisher | Taylor and Francis Group |
Peer Reviewed | Peer Reviewed |
Volume | 16 |
Issue | 7 |
Pages | 808-817 |
DOI | https://doi.org/10.1080/15592294.2020.1827715 |
Public URL | https://durham-repository.worktribe.com/output/1258211 |
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Copyright Statement
This is an Accepted Manuscript of an article published by Taylor & Francis in Epigenetics on 4 October 2020 available online: http://www.tandfonline.com/10.1080/15592294.2020.1827715
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