This is the peer reviewed version of the following article: Badshah, I. I., et al. "Differential expression of secreted factors SOSTDC1 and ADAMTS8 cause pro-fibrotic changes in linear morphoea fibroblasts." British Journal of Dermatology 0(ja)., which has been published in final form at https://doi.org/10.1111/bjd.17352. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsFunding: RO, IB and SB are funded by the Great Ormond Street Children's Charity. This research was supported by the NIHR Great Ormond Street Hospital Biomedical Research Centr

Badshah, I. I.

Brown, S.

Harper, J.

Inman, G.

Kinsler, V.

O'Shaughnessy, R.

Rose, A.

Sebire, N.

Way, B.

Weibel, L.

British Journal of Dermatology

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

Badshah, I.I.

O'Shaughnessy, R.F.L.

Enlighten

English

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

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

Badshah, I I

Brown, S

Weibel, L

Rose, A

Way, B

Sebire, N

Inman, G

Harper, J

O'Shaughnessy, R F L

ZORA

Enlighten: Publications

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

Badshah, II

Kinsler, V

O'Shaughnessy, R

UCL Discovery

O'Shaughnessy, RFL

Queen Mary Research Online

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.</p

Discovery Research Portal

Differential expression of secreted factors SOSTDC1 and ADAMTS8 cause pro-fibrotic changes in linear morphoea fibroblasts

https://discovery.dundee.ac.uk/ws/files/28840360/Badshah_et_al_2018_British_Journal_of_Dermatology.pdf

Differential expression of secreted factors SOSTDC1 and ADAMTS8 cause pro-fibrotic changes in linear morphoea fibroblasts

Abstract

Similar works

Full text

Available Versions

Enlighten

ZORA

Enlighten: Publications

UCL Discovery

Queen Mary Research Online

Discovery Research Portal

Discovery Research Portal