Differential expression of secreted factors SOSTDC1 and ADAMTS8 cause profibrotic changes in linear morphoea fibroblasts

Badshah, I.I., Brown, S., Weibel, L., Rose, A., Way, B., Sebire, N., Inman, G. , Harper, J. and O'Shaughnessy, R.F.L. (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. (doi: 10.1111/bjd.17352) (PMID:30367460)

Abstract

Background: Linear morphoea (LM) is a rare connective tissue disorder characterized by a line of thickened skin and subcutaneous tissue and can also affect the underlying muscle and bone. Little is known about the disease aetiology, with treatment currently limited to immune suppression, and disease recurrence post‐treatment is common. Objectives: In order to uncover new therapeutic avenues, the cell‐intrinsic changes in LM fibroblasts compared with site‐matched controls were characterized. Methods: We grew fibroblasts from site‐matched affected and unaffected regions from five patients with LM, we subjected them to gene expression analysis and investigation of SMAD signalling. Results: Fibroblasts from LM lesions showed increased migration, proliferation, altered collagen processing, and abnormally high basal levels of phosphorylated SMAD2, thereby rendering them less responsive to transforming growth factor (TGF)‐β1 and reducing the degree of myofibroblast differentiation, which is 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 knock‐down recapitulated the reduced TGF‐β1 responsiveness and LM fibroblast migration, while 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.

• Item Type: Articles
• Additional Information: R.O’S., I.I.B. and S.B. are funded by the Great Ormond Street Children’s Charity. This research was supported by the National Institute for Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Inman, Professor Gareth
• Authors: Badshah, I.I., Brown, S., Weibel, L., Rose, A., Way, B., Sebire, N., Inman, G., Harper, J., and O'Shaughnessy, R.F.L.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: British Journal of Dermatology
• Publisher: Wiley
• ISSN: 0007-0963
• ISSN (Online): 1365-2133
• Published Online: 26 October 2018
• Copyright Holders: Copyright © 2018 British Association of Dermatologists
• First Published: First published in British Journal of Dermatology 180(5): 1135-1149
• Publisher Policy: Reproduced in accordance with the publisher copyright policy