title: The molecular signature of impaired diabetic wound healing identifies serpinB3 as a healing biomarker.
abstract: OBJECTIVE
  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
  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.
authors: Department of Medicine, University of Padova, Via Giustiniani 2, 35128, Padova, Italy, gianpaolo.fadini@unipd.it.
authors: Gian Paolo
authors: GP
authors: Fadini
authors: Mattia
authors: M
authors: Albiero
authors: Renato
authors: R
authors: Millioni
authors: Nicol
authors: N
authors: Poncina
authors: Mauro
authors: M
authors: Rigato
authors: Rachele
authors: R
authors: Scotton
authors: Federico
authors: F
authors: Boscari
authors: Enrico
authors: E
authors: Brocco
authors: Giorgio
authors: G
authors: Arrigoni
authors: Gianmarco
authors: G
authors: Villano
authors: Cristian
authors: C
authors: Turato
authors: Alessandra
authors: A
authors: Biasiolo
authors: Patrizia
authors: P
authors: Pontisso
authors: Angelo
authors: A
authors: Avogaro
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism*; D017719:Diabetic Foot / Q000378:metabolism* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology*; D055815:Young Adult
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; D015843:Serpins; C051072:squamous cell carcinoma-related antigen