Thrombospondin-1 Is a Major Activator of TGF-β Signaling in Recessive Dystrophic Epidermolysis Bullosa Fibroblasts.

Autor:	Atanasova VS; Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Russell RJ; Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Webster TG; Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Cao Q; Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Agarwal P; Krystal Biotech Inc., Pittsburgh, Pennsylvania, USA., Lim YZ; Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Krishnan S; Krystal Biotech Inc., Pittsburgh, Pennsylvania, USA., Fuentes I; Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Fundación DEBRA Chile, Santiago, Chile., Guttmann-Gruber C; EB House Austria, Research Program for the Molecular Therapy of Genodermatoses, Department of Dermatology, University Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria., McGrath JA; St. John's Institute of Dermatology, King's College London (Guy's Campus), London, UK., Salas-Alanis JC; Instituto Dearmatologico de Jalisco, Guadalajara, Mexico., Fertala A; Department of Orthopedics, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., South AP; Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Electronic address: Andrew.South@Jefferson.edu.
Jazyk:	angličtina
Zdroj:	The Journal of investigative dermatology [J Invest Dermatol] 2019 Jul; Vol. 139 (7), pp. 1497-1505.e5. Date of Electronic Publication: 2019 Jan 23.
DOI:	10.1016/j.jid.2019.01.011
Abstrakt:	Mutations in the gene encoding collagen VII cause the devastating blistering disease recessive dystrophic epidermolysis bullosa (RDEB). RDEB is characterized by severe skin fragility and nonhealing wounds aggravated by scarring and fibrosis. We previously showed that TSP1 is increased in RDEB fibroblasts. Because transforming growth factor-β (TGF-β) signaling is also increased in RDEB, and TSP1 is known to activate TGF-β, we investigated the role of TSP1 in TGF-β signaling in RDEB patient cells. Knockdown of TSP1 reduced phosphorylation of smad3 (a downstream target of TGF-β signaling) in RDEB primary fibroblasts, whereas overexpression of collagen VII reduced phosphorylation of smad3. Furthermore, inhibition of TSP1 binding to the LAP/TGF-β complex decreased fibrosis in engineered extracellular matrix formed by RDEB fibroblasts, as evaluated by picrosirius red staining and analyses of birefringent collagen fibrillar deposits. We show that collagen VII binds TSP1, which could potentially limit TSP1-LAP association and subsequent TGF-β activation. Our study suggests a previously unreported mechanism for increased TGF-β signaling in the absence of collagen VII in RDEB patient skin. Moreover, these data identify TSP1 as a possible target for reducing fibrosis in the tumor-promoting dermal microenvironment of RDEB patients. (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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