Abstract
Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in COL7A1 resulting in reduced or absent type VII collagen, aberrant anchoring fibril formation and subsequent dermal-epidermal fragility. Here, we identify a significant decrease in PLOD3 expression and its encoded protein, the collagen modifying enzyme lysyl hydroxylase 3 (LH3), in RDEB. We show abundant LH3 localising to the basement membrane in normal skin which is severely depleted in RDEB patient skin. We demonstrate expression is in-part regulated by endogenous type VII collagen and that, in agreement with previous studies, even small reductions in LH3 expression lead to significantly less secreted LH3 protein. Exogenous type VII collagen did not alter LH3 expression in cultured RDEB keratinocytes and we show that RDEB patients receiving bone marrow transplantation who demonstrate significant increase in type VII collagen do not show increased levels of LH3 at the basement membrane. Our data report a direct link between LH3 and endogenous type VII collagen expression concluding that reduction of LH3 at the basement membrane in patients with RDEB will likely have significant implications for disease progression and therapeutic intervention.
Highlights
Epidermolysis bullosa (EB) is a heterogeneous group of inherited disorders that can be either localized within skin or systemic in presentation and severe cases are often life-threatening [1]
Antibodies raised against lysyl hydroxylase 3 (LH3) revealed striking localization to the dermal-epidermal junction in normal skin which was significantly reduced in Recessive dystrophic epidermolysis bullosa (RDEB) patients (Fig 1A)
A reduction in LH3 localization at the basement membrane is evident in COL7A1 -/- epidermis isolated from a humanized murine model of RDEB (Fig 1B; for details on creation of this novel RDEB model see S1–S3 Figs)
Summary
Epidermolysis bullosa (EB) is a heterogeneous group of inherited disorders that can be either localized within skin or systemic in presentation and severe cases are often life-threatening [1]. This study demonstrated that increased type VII collagen is evident in patient skin after transplantation, anchoring fibrils (the major structural component resulting from type VII collagen processing) are absent some 100 days post procedure [2] suggesting that the mere presence of increased type VII collagen was insufficient to recapitulate the ultrastructural features of fully functional skin in RDEB patients receiving therapy. This indicates that further refinements to the procedure or additional interventions are required for a complete cure
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