Badshah, II;
Brown, S;
Weibel, L;
Rose, A;
Way, B;
Sebire, N;
Inman, G;
... O'Shaughnessy, R; + view all
(2019)
Differential expression of secreted factors SOSTDC1 and ADAMTS8 cause profibrotic changes in linear morphoea fibroblasts.
British Journal of Dermatology
, 180
(5)
pp. 1135-1149.
10.1111/bjd.17352.
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Abstract
BACKGROUND: Linear morphoea (LM) is a rare connective tissue disorder characterised by a line of thickened skin and subcutaneous tissue and can also affect the underlying muscle and bone. Little is known about disease aetiology, with treatment currently limited to immune suppression, and disease recurrence post-treatment is common. OBJECTIVE: To uncover new therapeutic avenues, the cell intrinsic changes in LM fibroblasts compared to site-matched controls was characterised. METHODS: We grew fibroblasts from site matched affected and unaffected regions from 5 linear morphoea patients, we subjected them to gene expression analysis and investigation of SMAD signalling. RESULTS: Fibroblasts from LM lesions showed increased migration, proliferation, altered collagen processing, as well as abnormally high basal levels of phosphorylated SMAD2, thereby rendering them less responsive to TGF-β1 and reducing the degree of myofibroblast differentiation, a key component of the wound healing and scarring process in normal skin. Conditioned media from normal fibroblasts could reverse LM affected fibroblast migration and proliferation, suggesting that the LM phenotype is driven by an altered secretome. Gene array analysis and RNA-Seq indicated upregulation of ADAMTS8 and downregulation of FRAS1 and SOSTDC1. SOSTDC1 knockdown recapitulated the reduced TGF-β1 responsiveness and LM fibroblast migration, whilst overexpression of ADAMTS8 induced myofibroblast markers. CONCLUSIONS: We demonstrate that cell-intrinsic changes in the LM fibroblast secretome lead to changes observed in the disease, and that secretome modulation could be a viable therapeutic approach in the treatment of LM. This article is protected by copyright. All rights reserved.
| Type: | Article |
|---|---|
| Title: | Differential expression of secreted factors SOSTDC1 and ADAMTS8 cause profibrotic changes in linear morphoea fibroblasts |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/bjd.17352 |
| Publisher version: | https://doi.org/10.1111/bjd.17352 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Linear morphoea, TGF-β, fibrosis, migration, proliferation, secreted proteins |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Population, Policy and Practice Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10061162 |
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