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01.09.2014 | Article | Ausgabe 9/2014

Diabetologia 9/2014

The molecular signature of impaired diabetic wound healing identifies serpinB3 as a healing biomarker

Zeitschrift:
Diabetologia > Ausgabe 9/2014
Autoren:
Gian Paolo Fadini, Mattia Albiero, Renato Millioni, Nicol Poncina, Mauro Rigato, Rachele Scotton, Federico Boscari, Enrico Brocco, Giorgio Arrigoni, Gianmarco Villano, Cristian Turato, Alessandra Biasiolo, Patrizia Pontisso, Angelo Avogaro
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s00125-014-3300-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Abstract

Aims/hypothesis

Chronic foot ulceration is a severe complication of diabetes, driving morbidity and mortality. The mechanisms underlying delaying wound healing in diabetes are incompletely understood and tools to identify such pathways are eagerly awaited.

Methods

Wound biopsies were obtained from 75 patients with diabetic foot ulcers. Matched subgroups of rapidly healing (RH, n = 17) and non-healing (NH, n = 11) patients were selected. Proteomic analysis was performed by labelling with isobaric tag for relative and absolute quantification and mass spectrometry. Differentially expressed proteins were analysed in NH vs RH for identification of pathogenic pathways. Individual sample gene/protein validation and in vivo validation of candidate pathways in mouse models were carried out.

Results

Pathway analyses were conducted on 92/286 proteins that were differentially expressed in NH vs RH. The following pathways were enriched in NH vs RH patients: apoptosis, protease inhibitors, epithelial differentiation, serine endopeptidase activity, coagulation and regulation of defence response. SerpinB3 was strongly upregulated in RH vs NH wounds, validated as protein and mRNA in individual samples. To test the relevance of serpinB3 in vivo, we used a transgenic mouse model with α1-antitrypsin promoter-driven overexpression of human SERPINB3. In this model, wound healing was unaffected by SERPINB3 overexpression in non-diabetic or diabetic mice with or without hindlimb ischaemia. In an independent validation cohort of 47 patients, high serpinB3 protein content was confirmed as a biomarker of healing improvement.

Conclusions/interpretation

We provide a benchmark for the unbiased discovery of novel molecular targets and biomarkers of impaired diabetic wound healing. High serpinB3 protein content was found to be a biomarker of successful healing in diabetic patients.

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