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Histone deacetylase inhibition mitigates fibrosis-driven disease progression in recessive dystrophic epidermolysis bullosa

ABSTRACT: Recessive dystrophic epidermolysis bullosa (RDEB) is a mucocutaneous blistering disease due to type VII collagen gene mutations. Transforming growth factor-β (TGF-β)-dependent fibrosis is responsible for severe RDEB complications. Reduced histone acetylation is a hallmark of fibrosis in pathologies affecting organs other than skin, where inhibition of histone deacetylses (HDACs) proved effective in reverting fibrosis. Here, HDAC inhibitor (HDACi) ability to counteract RDEB progression was investigated. We found that histone acetylation is decreased in RDEB skin and fibroblasts. Treatment with two HDACis, valproic acid (VPA) and Givinostat, counteracts RDEB fibroblast fibrotic traits, including contractility, α-smooth muscle actin expression, TGF-β1 release, and proliferation. Moreover, systemic VPA administration mitigates severe manifestations (corneal opacification and digit loss) in a RDEB mouse model. This effect associates with inhibition of skin fibrosis (presence of subcutaneous fat, thinner collagen bundles, decreased expression of fibrotic markers). Proteomic analysis of mouse skin revealed that VPA treatment decreases expression of genes involved in protein synthesis and increases levels of proteins with role in immune response. These findings highlight epigenetic changes as contributing to RDEB pathogenesis and disclose molecular mechanisms leading to skin fibrosis. Treatment with HDACi may represent a disease modifier therapeutic approach for RDEB and other skin fibrotic disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239569 | GEO | 2024/09/02

REPOSITORIES: GEO

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Project description:Recessive dystrophic epidermolysis bullosa (RDEB) is a genodermatosis characterized by fragile skin forming blisters that heal invariably with scars. It is due to mutations in the COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils connecting the cutaneous basement membrane to the dermis. Identical COL7A1 mutations often result in inter- and intra-familial disease variability, suggesting that additional modifiers contribute to RDEB course. Here, we studied a monozygotic twin pair with RDEB presenting markedly different phenotypic manifestations, while expressing similar amounts of collagen VII. Genome-wide expression analysis in twins' fibroblasts showed differential expression of genes associated with TGF-β pathway inhibition. In particular, decorin, a skin matrix component with anti-fibrotic properties, was found to be more expressed in the less affected twin. Accordingly, fibroblasts from the more affected sibling manifested a profibrotic and contractile phenotype characterized by enhanced α-smooth muscle actin and plasminogen activator inhibitor 1 expression, collagen I release and collagen lattice contraction. These cells also produced increased amounts of proinflammatory cytokines interleukin 6 and monocyte chemoattractant protein-1. Both TGF-β canonical (Smads) and non-canonical (MAPKs) pathways were basally more activated in the fibroblasts of the more affected twin. The profibrotic behaviour of these fibroblasts was suppressed by decorin delivery to cells. Our data show that the amount of type VII collagen is not the only determinant of RDEB clinical severity, and indicate an involvement of TGF-β pathways in modulating disease variability. Moreover, our findings identify decorin as a possible anti-fibrotic/inflammatory agent for RDEB therapeutic intervention. Primary fibroblast cultures from biopsies from two twins affected by recessive dystrophic epidermolysis bullosa were analyzed. Each hybridization was performed in biological triplicate and in technical duplicate.

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Histone deacetylase inhibition mitigates fibrosis-driven disease progression in recessive dystrophic epidermolysis bullosa

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