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 language | English |
|---|---|
| Journal | Matrix Biology |
| DOIs | |
| Publication status | Accepted/In press - Jan 1 2018 |
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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 journal › Article
}
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 -