Decorin counteracts disease progression in mice with recessive dystrophic epidermolysis bullosa

Francesca Cianfarani, Emanuela De Domenico, Alexander Nyström, Simona Mastroeni, Damiano Abeni, Enke Baldini, Salvatore Ulisse, Paolo Uva, Leena Bruckner-Tuderman, Giovanna Zambruno, Daniele Castiglia, Teresa Odorisio

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Loss-of-function mutations in the gene encoding type VII collagen underlie recessive dystrophic epidermolysis bullosa (RDEB), a disease characterized by skin and mucosal blistering, impaired wound healing, and diffuse dermal inflammation and fibrosis. Transforming growth factor-β signaling plays a crucial role in determining RDEB fibrotic microenvironment that leads to the development of disabling secondary disease manifestations, including hand and foot deformities. Experimental findings indicate that expression levels of decorin, a small leucine-rich proteoglycan and an endogenous TGF-β inhibitor, can modulate RDEB disease phenotype by contrasting dermal fibroblast fibrotic behavior. In this study, the ability of decorin to modify RDEB course was investigated by systemically treating RDEB mice with a lentivirus expressing human decorin. Overexpressed decorin was able to enhance survival, and to limit digit contraction and the development of paw deformities. These effects were associated with decreased TGF-β1 levels and TGF-β signaling activation. Fibrotic traits were strongly reduced in paw skin and also attenuated in the non-chronically injured back skin. However, the expression of pro-inflammatory proteins was not decreased in both paw and back skin. Our findings confirm TGF-β role in promoting fibrosis and disease progression in RDEB, and show that decorin counteracts disease manifestations by inhibiting TGF-β activation. More generally, our data indicate that modifying extracellular matrix composition is an option to improve RDEB disease course.

Original languageEnglish
JournalMatrix Biology
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Epidermolysis Bullosa Dystrophica
Decorin
Disease Progression
Skin
Fibrosis
Hand Deformities
Collagen Type VII
Foot Deformities
Lentivirus
Aptitude
Transforming Growth Factors
Skin Diseases
Wound Healing
Extracellular Matrix
Fibroblasts
Inflammation
Phenotype
Mutation
Survival

Keywords

  • Disease modifying therapy
  • Extracellular matrix
  • Fibrosis
  • Genodermatoses
  • Inflammation
  • Skin repair

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Decorin counteracts disease progression in mice with recessive dystrophic epidermolysis bullosa. / Cianfarani, Francesca; De Domenico, Emanuela; Nyström, Alexander; Mastroeni, Simona; Abeni, Damiano; Baldini, Enke; Ulisse, Salvatore; Uva, Paolo; Bruckner-Tuderman, Leena; Zambruno, Giovanna; Castiglia, Daniele; Odorisio, Teresa.

In: Matrix Biology, 01.01.2018.

Research output: Contribution to journalArticle

Cianfarani, Francesca ; De Domenico, Emanuela ; Nyström, Alexander ; Mastroeni, Simona ; Abeni, Damiano ; Baldini, Enke ; Ulisse, Salvatore ; Uva, Paolo ; Bruckner-Tuderman, Leena ; Zambruno, Giovanna ; Castiglia, Daniele ; Odorisio, Teresa. / Decorin counteracts disease progression in mice with recessive dystrophic epidermolysis bullosa. In: Matrix Biology. 2018.
@article{cd73096c62ce44f3b2372ab0c19c0902,
title = "Decorin counteracts disease progression in mice with recessive dystrophic epidermolysis bullosa",
abstract = "Loss-of-function mutations in the gene encoding type VII collagen underlie recessive dystrophic epidermolysis bullosa (RDEB), a disease characterized by skin and mucosal blistering, impaired wound healing, and diffuse dermal inflammation and fibrosis. Transforming growth factor-β signaling plays a crucial role in determining RDEB fibrotic microenvironment that leads to the development of disabling secondary disease manifestations, including hand and foot deformities. Experimental findings indicate that expression levels of decorin, a small leucine-rich proteoglycan and an endogenous TGF-β inhibitor, can modulate RDEB disease phenotype by contrasting dermal fibroblast fibrotic behavior. In this study, the ability of decorin to modify RDEB course was investigated by systemically treating RDEB mice with a lentivirus expressing human decorin. Overexpressed decorin was able to enhance survival, and to limit digit contraction and the development of paw deformities. These effects were associated with decreased TGF-β1 levels and TGF-β signaling activation. Fibrotic traits were strongly reduced in paw skin and also attenuated in the non-chronically injured back skin. However, the expression of pro-inflammatory proteins was not decreased in both paw and back skin. Our findings confirm TGF-β role in promoting fibrosis and disease progression in RDEB, and show that decorin counteracts disease manifestations by inhibiting TGF-β activation. More generally, our data indicate that modifying extracellular matrix composition is an option to improve RDEB disease course.",
keywords = "Disease modifying therapy, Extracellular matrix, Fibrosis, Genodermatoses, Inflammation, Skin repair",
author = "Francesca Cianfarani and {De Domenico}, Emanuela and Alexander Nystr{\"o}m and Simona Mastroeni and Damiano Abeni and Enke Baldini and Salvatore Ulisse and Paolo Uva and Leena Bruckner-Tuderman and Giovanna Zambruno and Daniele Castiglia and Teresa Odorisio",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.matbio.2018.12.001",
language = "English",
journal = "Matrix Biology",
issn = "0945-053X",
publisher = "Elsevier B.V.",

}

TY - JOUR

T1 - Decorin counteracts disease progression in mice with recessive dystrophic epidermolysis bullosa

AU - Cianfarani, Francesca

AU - De Domenico, Emanuela

AU - Nyström, Alexander

AU - Mastroeni, Simona

AU - Abeni, Damiano

AU - Baldini, Enke

AU - Ulisse, Salvatore

AU - Uva, Paolo

AU - Bruckner-Tuderman, Leena

AU - Zambruno, Giovanna

AU - Castiglia, Daniele

AU - Odorisio, Teresa

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Loss-of-function mutations in the gene encoding type VII collagen underlie recessive dystrophic epidermolysis bullosa (RDEB), a disease characterized by skin and mucosal blistering, impaired wound healing, and diffuse dermal inflammation and fibrosis. Transforming growth factor-β signaling plays a crucial role in determining RDEB fibrotic microenvironment that leads to the development of disabling secondary disease manifestations, including hand and foot deformities. Experimental findings indicate that expression levels of decorin, a small leucine-rich proteoglycan and an endogenous TGF-β inhibitor, can modulate RDEB disease phenotype by contrasting dermal fibroblast fibrotic behavior. In this study, the ability of decorin to modify RDEB course was investigated by systemically treating RDEB mice with a lentivirus expressing human decorin. Overexpressed decorin was able to enhance survival, and to limit digit contraction and the development of paw deformities. These effects were associated with decreased TGF-β1 levels and TGF-β signaling activation. Fibrotic traits were strongly reduced in paw skin and also attenuated in the non-chronically injured back skin. However, the expression of pro-inflammatory proteins was not decreased in both paw and back skin. Our findings confirm TGF-β role in promoting fibrosis and disease progression in RDEB, and show that decorin counteracts disease manifestations by inhibiting TGF-β activation. More generally, our data indicate that modifying extracellular matrix composition is an option to improve RDEB disease course.

AB - Loss-of-function mutations in the gene encoding type VII collagen underlie recessive dystrophic epidermolysis bullosa (RDEB), a disease characterized by skin and mucosal blistering, impaired wound healing, and diffuse dermal inflammation and fibrosis. Transforming growth factor-β signaling plays a crucial role in determining RDEB fibrotic microenvironment that leads to the development of disabling secondary disease manifestations, including hand and foot deformities. Experimental findings indicate that expression levels of decorin, a small leucine-rich proteoglycan and an endogenous TGF-β inhibitor, can modulate RDEB disease phenotype by contrasting dermal fibroblast fibrotic behavior. In this study, the ability of decorin to modify RDEB course was investigated by systemically treating RDEB mice with a lentivirus expressing human decorin. Overexpressed decorin was able to enhance survival, and to limit digit contraction and the development of paw deformities. These effects were associated with decreased TGF-β1 levels and TGF-β signaling activation. Fibrotic traits were strongly reduced in paw skin and also attenuated in the non-chronically injured back skin. However, the expression of pro-inflammatory proteins was not decreased in both paw and back skin. Our findings confirm TGF-β role in promoting fibrosis and disease progression in RDEB, and show that decorin counteracts disease manifestations by inhibiting TGF-β activation. More generally, our data indicate that modifying extracellular matrix composition is an option to improve RDEB disease course.

KW - Disease modifying therapy

KW - Extracellular matrix

KW - Fibrosis

KW - Genodermatoses

KW - Inflammation

KW - Skin repair

UR - http://www.scopus.com/inward/record.url?scp=85058396239&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058396239&partnerID=8YFLogxK

U2 - 10.1016/j.matbio.2018.12.001

DO - 10.1016/j.matbio.2018.12.001

M3 - Article

AN - SCOPUS:85058396239

JO - Matrix Biology

JF - Matrix Biology

SN - 0945-053X

ER -