RT Journal Article
T1 Mechanistic interrogation of mutation-independent disease modulators of RDEB identifies the small leucine-rich proteoglycan PRELP as a TGF-beta antagonist and inhibitor of fibrosis
A1 Chacon Solano, Esteban Gonzalo
A1 León Canseco, Carlos
A1 Carretero, M.
A1 García Díez, Marta
A1 Sánchez Domínguez, R.
A1 Quero, F.
A1 Méndez Jiménez, Estela
A1 Bonafont Aragó, José
A1 Ruiz Mezcua, María Belén
A1 Escámez Toledano, María José
A1 Larcher Laguzzi, Fernando
A1 Rio Nechaevsky, Marcelan Andra del
AB Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic extracellular matrix disease caused by deficiency in type VII collagen (Col VII). The disease manifests with devastating mucocutaneous fragility leading to progressive fibrosis and metastatic squamous cell carcinomas. Although Col VII abundance is considered the main predictor of symptom course, previous studies have revealed the existence of mutation-independent mechanisms that control disease progression. Here, to investigate and validate new molecular modifiers of wound healing and fibrosis in a natural human setting, and toward development of disease-modulating treatment of RDEB, we performed gene expression profiling of primary fibroblast from RDEB siblings with marked phenotypic variations, despite having equal COL7A1 genotype. Gene enrichment analysis suggested that severe RDEB was associated with enhanced response to TGFB stimulus, oxidoreductase activity, and cell contraction. Consistently, we found an increased response to TGFB, higher levels of basal and induced reactive oxygen species (ROS), and greater contractile ability in collagen lattices in RDEB fibroblasts (RDEBFs) from donors with severe RDEB vs mild RDEB. Treatment with antioxidants allowed a reduction of the pro-fibrotic and contractile phenotype. Importantly, our analyses revealed higher expression and deposition in skin of the relatively uncharacterized small leucine-rich extracellular proteoglycan PRELP/prolargin associated with milder RDEB manifestations. Mechanistic investigations showed that PRELP effectively attenuated fibroblasts' response to TGFB stimulus and cell contractile capacity. Moreover, PRELP overexpression in RDEBFs enhanced RDEB keratinocyte attachment to fibroblast-derived extracellular matrix in the absence of Col VII. Our results highlight the clinical relevance of pro-oxidant status and hyper-responsiveness to TGFB in RDEB severity and progression. Of note, our study also reveals PRELP as a novel and natural TGFB antagonist with a likely dermo-epidermal pro-adhesive capacity.
PB Elsevier
SN 0945-053X
YR 2022
FD 2022-06-30
LK https://hdl.handle.net/10016/38216
UL https://hdl.handle.net/10016/38216
LA eng
NO This study was supported in part by grants from Spanish Ministry of Science and Innovation and European Regional Development fund (PID2020-119792RB-I00); Institute of Health Carlos III (RD21/0001/0022, Spanish Network of Advanced Therapies; TERAV-ISCIII) funded by NextGenerationEU: Recovery, Transformation and Resilience Plan; and DEBRA Austria, co-funded by DEBRA Sweden, EB-LOPPET and supported by EB Research Network (León-1). Funding for APC: Universidad Carlos III de Madrid (Read & Publish Agreement CRUE-CSIC 2022).
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RD 27 jul. 2024