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

I. I. Badshah, S. Brown, L. Weibel, A. Rose, B. Way, N. Sebire, G. Inman, J. Harper, V. Kinsler, R. O'Shaughnessy (Lead / Corresponding author)

Research output: Contribution to journalArticle

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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.

Original languageEnglish
JournalBritish Journal of Dermatology
Early online date26 Oct 2018
DOIs
Publication statusE-pub ahead of print - 26 Oct 2018

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Localized Scleroderma
Fibroblasts
Myofibroblasts
Transforming Growth Factors
Therapeutics
Skin
Immune System Diseases
Subcutaneous Tissue
Conditioned Culture Medium
Connective Tissue
Wound Healing
Cicatrix
Up-Regulation
Collagen
Down-Regulation
RNA
Phenotype
Gene Expression
Bone and Bones
Recurrence

Keywords

  • Linear morphoea
  • fibrosis
  • migration
  • proliferation
  • secreted proteins
  • TGF-β

Cite this

Badshah, I. I. ; Brown, S. ; Weibel, L. ; Rose, A. ; Way, B. ; Sebire, N. ; Inman, G. ; Harper, J. ; Kinsler, V. ; O'Shaughnessy, R. / Differential expression of secreted factors SOSTDC1 and ADAMTS8 cause pro-fibrotic changes in linear morphoea fibroblasts. In: British Journal of Dermatology. 2018.
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title = "Differential expression of secreted factors SOSTDC1 and ADAMTS8 cause pro-fibrotic changes in linear morphoea fibroblasts",
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.",
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author = "Badshah, {I. I.} and S. Brown and L. Weibel and A. Rose and B. Way and N. Sebire and G. Inman and J. Harper and V. Kinsler and R. O'Shaughnessy",
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Differential expression of secreted factors SOSTDC1 and ADAMTS8 cause pro-fibrotic changes in linear morphoea fibroblasts. / Badshah, I. I.; Brown, S.; Weibel, L.; Rose, A.; Way, B.; Sebire, N.; Inman, G.; Harper, J.; Kinsler, V.; O'Shaughnessy, R. (Lead / Corresponding author).

In: British Journal of Dermatology, 26.10.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Differential expression of secreted factors SOSTDC1 and ADAMTS8 cause pro-fibrotic changes in linear morphoea fibroblasts

AU - Badshah, I. I.

AU - Brown, S.

AU - Weibel, L.

AU - Rose, A.

AU - Way, B.

AU - Sebire, N.

AU - Inman, G.

AU - Harper, J.

AU - Kinsler, V.

AU - O'Shaughnessy, R.

N1 - Funding: RO, IB, and SB are funded by the Great Ormond Street Children's Charity. This reserach was supported by NIHR Great Ormond Street Hospital Biomedical Research Centre.

PY - 2018/10/26

Y1 - 2018/10/26

N2 - 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.

AB - 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.

KW - Linear morphoea

KW - fibrosis

KW - migration

KW - proliferation

KW - secreted proteins

KW - TGF-β

U2 - 10.1111/bjd.17352

DO - 10.1111/bjd.17352

M3 - Article

C2 - 30367460

JO - British Journal of Dermatology

JF - British Journal of Dermatology

SN - 0007-0963

ER -