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Treatment of keratinocytes with 4-phenylbutyrate in epidermolysis bullosa: Lessons for therapies in keratin disorders.

ABSTRACT: BACKGROUND:Missense mutations in keratin 5 and 14 genes cause the severe skin fragility disorder epidermolysis bullosa simplex (EBS) by collapsing of the keratin cytoskeleton into cytoplasmic protein aggregates. Despite intense efforts, no molecular therapies are available, mostly due to the complex phenotype of EBS, comprising cell fragility, diminished adhesion, skin inflammation and itch. METHODS:We extensively characterized KRT5 and KRT14 mutant keratinocytes from patients with severe generalized EBS following exposure to the chemical chaperone 4-phenylbutyrate (4-PBA). FINDINGS:4-PBA diminished keratin aggregates within EBS cells and ameliorated their inflammatory phenotype. Chemoproteomics of 4-PBA-treated and untreated EBS cells revealed reduced IL1? expression- but also showed activation of Wnt/?-catenin and NF-kB pathways. The abundance of extracellular matrix and cytoskeletal proteins was significantly altered, coinciding with diminished keratinocyte adhesion and migration in a 4-PBA dose-dependent manner. INTERPRETATION:Together, our study reveals a complex interplay of benefits and disadvantages that challenge the use of 4-PBA in skin fragility disorders.

SUBMITTER: Sporrer M

PROVIDER: S-EPMC6603805 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Treatment of keratinocytes with 4-phenylbutyrate in epidermolysis bullosa: Lessons for therapies in keratin disorders.

Spörrer Marina M Prochnicki Ania A Tölle Regine C RC Nyström Alexander A Esser Philipp R PR Homberg Melanie M Athanasiou Ioannis I Zingkou Eleni E Schilling Achim A Gerum Richard R Thievessen Ingo I Winter Lilli L Bruckner-Tuderman Leena L Fabry Ben B Magin Thomas M TM Dengjel Jörn J Schröder Rolf R Kiritsi Dimitra D

EBioMedicine 20190509

<h4>Background</h4>Missense mutations in keratin 5 and 14 genes cause the severe skin fragility disorder epidermolysis bullosa simplex (EBS) by collapsing of the keratin cytoskeleton into cytoplasmic protein aggregates. Despite intense efforts, no molecular therapies are available, mostly due to the complex phenotype of EBS, comprising cell fragility, diminished adhesion, skin inflammation and itch.<h4>Methods</h4>We extensively characterized KRT5 and KRT14 mutant keratinocytes from patients wit ...[more]

PMID: 31078522

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Project description:Epidermolysis bullosa (EB) includes a group of rare skin diseases characterized by skin fragility with bullous formation in the skin, in response to minor mechanical injury, as well as varying degrees of involvement of the mucous membranes of the internal organs. EB is classified into simplex, junctional, dystrophic and mixed. The impact of the disease on patients is both physical and psychological, with the result that their quality of life is constantly affected. Unfortunately, there are still no approved treatments available to confront the disease, and treatment focuses on improving the symptoms with topical treatments to avoid complications and other infections. Stem cells are undifferentiated cells capable of producing, maintaining and replacing terminally differentiated cells and tissues. Stem cells can be isolated from embryonic or adult tissues, including skin, but are also produced by genetic reprogramming of differentiated cells. Preclinical and clinical research has recently greatly improved stem cell therapy, making it a promising treatment option for various diseases in which current medical treatments fail to cure, prevent progression, or alleviate symptoms. So far, stem cells from different sources, mainly hematopoietic and mesenchymal, autologous or heterologous have been used for the treatment of the most severe forms of the disease each one of them with some beneficial effects. However, the mechanisms through which stem cells exert their beneficial role are still unknown or incompletely understood and most importantly further research is required to evaluate the effectiveness and safety of these treatments. The transplantation of skin grafts to patients produced by gene-corrected autologous epidermal stem cells has been proved to be rather successful for the treatment of skin lesions in the long term in a limited number of patients. Nevertheless, these treatments do not address the internal epithelia-related complications manifested in patients with more severe forms.

Dataset Information

Treatment of keratinocytes with 4-phenylbutyrate in epidermolysis bullosa: Lessons for therapies in keratin disorders.

Publications

Treatment of keratinocytes with 4-phenylbutyrate in epidermolysis bullosa: Lessons for therapies in keratin disorders.

Similar Datasets

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