Monozygotic twins discordant for recessive dystrophic epidermolysis bullosa phenotype highlight the role of TGF-β signalling in modifying disease severity

Abstract

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.

miR-29 Regulates Type VII Collagen in Recessive Dystrophic Epidermolysis Bullosa

“…TGF-β signaling leads to phosphorylation of downstream effector SMAD proteins, of which, activated SMAD3/4 bind to COL7A1 promoter and promote COL7A1 transcription. Furthermore, TGF-β activation influences RDEB disease severity through increased type 1 collagen and decreased decorin expression (Odorisio et al , 2014). Previous studies have also demonstrated that TGF-β signaling results in a decrease in miR-29 expression through inhibition of transcription via binding of SMAD3 to the miR-29 promoter region (Qin et al , 2011, Zhou et al , 2012).…”

Novel and emerging therapies in the treatment of recessive dystrophic epidermolysis bullosa

“…As a result of reduced TGF-β activity, there was significantly slower progression to fibrotic digit fusion and mitten deformities (76). The role of TGF-β signalling has been highlighted as a potential modifier of disease severity following the study of monozygotic twins with RDEB with markedly different clinical phenotypes and similar amounts of C7 expression (77). In this study, genome wide expression analysis in twins' fibroblasts showed differential expression of the genes associated with TGF-β pathway inhibition.…”

Combinatorial Omics Analysis Reveals Perturbed Lysosomal Homeostasis in Collagen VII-deficient Keratinocytes

“…Deficiency of the ECM protein C7 in DEB leads to substantial dermal changes: impaired skin regeneration and TGF--driven fibrosis that facilitates aggressive squamous cell carcinoma (SCC) (8)(9)(10)12,38,40). However, C7 is both a dermal and an epidermal product and so far the direct cellular changes that loss of C7 evokes in epidermal keratinocytes remained limitedly studied (7,38).…”

“…It has become apparent that progressive TGF--mediated soft tissue fibrosis plays a major role in disease evolution of DEB (11,12). In other diseases epithelial dysfunction is known to be a major instigator of fibrosis (13).…”