Low-dose calcipotriol can elicit wound closure, anti-microbial, and anti-neoplastic effects in epidermolysis bullosa keratinocytes

Christina Guttmann‐Gruber ,Clemens Hüttner,Josefina Piñón Hofbauer,Dirk Strunk,Julia Reichelt,Martin Laimer,John E.a Common ,A.a.o Tay ,Peter Schnitzhofer,B Tockner ,Peter Hofbauer,Alfred Klausegger,Anja Diem,Roland Lang,Johann Bauer ,Martin Wolkersdorfer,Andrea Trost,Simon Denil ,Cornelia Scharler,Jenny Breitenbach

doi:10.1038/s41598-018-31823-6

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) patients suffer from chronic and repeatedly infected wounds predisposing them to the development of aggressive and life-threatening skin cancer in these areas. Vitamin D3 is an often neglected but critical factor for wound healing. Intact skin possesses the entire enzymatic machinery required to produce active 1-alpha,25-dihydroxyvitamin D3 (calcitriol), underscoring its significance to proper skin function. Injury enhances calcitriol production, inducing the expression of calcitriol target genes including the antimicrobial peptide cathelicidin (hCAP18), an essential component of the innate immune system and an important wound healing factor. We found significantly reduced hCAP18 expression in a subset of RDEB keratinocytes which could be restored by calcipotriol treatment. Reduced scratch closure in RDEB cell monolayers was enhanced up to 2-fold by calcipotriol treatment, and the secretome of calcipotriol-treated cells additionally showed increased antimicrobial activity. Calcipotriol exhibited anti-neoplastic effects, suppressing the clonogenicity and proliferation of RDEB tumor cells. The combined wound healing, anti-microbial, and anti-neoplastic effects indicate that calcipotriol may represent a vital therapeutic option for RDEB patients which we could demonstrate in a single-patient observation study.

Highlights

Recessive dystrophic epidermolysis bullosa (RDEB) patients suffer from chronic and repeatedly infected wounds predisposing them to the development of aggressive and life-threatening skin cancer in these areas
Normal human keratinocytes (NHK) and RDEB keratinocytes were treated for 72 hrs with increasing concentrations of calcipotriol and proliferation was measured by MTT assay
In order to provide evidence that calcipotriol treatment could have a clinical benefit in RDEB, we investigated the responsiveness of 5 different RDEB keratinocyte cell lines to calcipotriol using induction of cathelicidin, a direct vitamin D receptor (VDR)-target gene, as a readout

Summary

Introduction

Recessive dystrophic epidermolysis bullosa (RDEB) patients suffer from chronic and repeatedly infected wounds predisposing them to the development of aggressive and life-threatening skin cancer in these areas. Injury enhances calcitriol production, inducing the expression of calcitriol target genes including the antimicrobial peptide cathelicidin (hCAP18), an essential component of the innate immune system and an important wound healing factor. Skin injury further enhances production of calcitriol, triggering the expression of VDR-target genes involved in wound healing, most notably the antimicrobial peptide cathelicidin (CAMP)[14]. Vitamin D3 enables keratinocytes to recognize and respond to wounding and infection by enhancing antimicrobial defenses and initiating repair processes These findings are relevant in the context of RDEB, as limited sun exposure due to wound dressings and reduced outdoor activity of patients could lead to a local vitamin D3 deficiency in the skin[21]. Calcipotriol exhibited anti-neoplastic effects against RDEB tumor cells, underscoring its potential as a safe therapeutic option for managing non-healing wounds in this patient group

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Results

Conclusion