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microRNA27a-3p mediates reduction of the Wnt antagonist sFRP-1 in systemic sclerosis.

Henderson, John and Wilkinson, Sarah and Przyborski, Stefan and Stratton, Richard and O’Reilly, Steven (2021) 'microRNA27a-3p mediates reduction of the Wnt antagonist sFRP-1 in systemic sclerosis.', Epigenetics., 16 (7). pp. 808-817.

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.

Item Type:Article
Full text:(AM) Accepted Manuscript
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Status:Peer-reviewed
Publisher Web site:https://doi.org/10.1080/15592294.2020.1827715
Publisher 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
Date accepted:18 August 2020
Date deposited:30 October 2020
Date of first online publication:04 October 2020
Date first made open access:04 October 2021

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