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J Invest Dermatol. 2019 Jan 23. pii: S0022-202X(19)30028-4. doi: 10.1016/j.jid.2019.01.011. [Epub ahead of print]

Thrombospondin-1 is a major activator of TGF-beta signaling in recessive dystrophic epidermolysis bullosa fibroblasts.

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Department of Dermatology & Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA.
Krystal Biotech Inc, Pittsburg, PA.
Department of Dermatology & Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA; Fundación DEBRA Chile, Santiago, Chile.
EB House Austria, Research Program for the Molecular Therapy of Genodermatoses, Department of Dermatology, University Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria.
St. John's Institute of Dermatology, King's College London (Guy's Campus), London, UK.
Dermatology, Hospital ISSSTE Lic. Adolfo Lopez Mateos, CdMx, Mexico.
Department of Orthopedics, Thomas Jefferson University, Philadelphia, PA.
Department of Dermatology & Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA. Electronic address:


Mutations in the gene encoding collagen VII (C7) cause the devastating blistering disease recessive dystrophic epidermolysis bullosa (RDEB). RDEB is characterized by severe skin fragility and non-healing wounds aggravated by scarring and fibrosis. We previously demonstrated that thrombospondin-1 (TSP1) is increased in RDEB fibroblasts. Because transforming growth factor-beta (TGFβ) signaling is also increased in RDEB, and TSP1 is known to activate TGFβ, we investigated the role of TSP1 in TGFβ signaling in RDEB patient cells. Knock-down of TSP1 reduced phosphorylation of smad3 (a downstream target of TGFβ signaling) in RDEB primary fibroblasts, while over-expression of C7 reduced phosphorylation of smad3. Furthermore, inhibition of TSP1 binding to the latency-associated protein (LAP)/TGFβ 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 demonstrate that C7 binds TSP1, which could potentially limit TSP1-LAP association and subsequent TGFβ activation. Our study suggests a previously unreported mechanism for increased TGFβ signaling in the absence of C7 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.


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