Open AccessExpression of cell proliferation cycle negative regulators in fibroblasts of an ischemic diabetic foot ulcer. A clinical case report
Author(s) -
BerlangaAcosta Jorge,
MendozaMari Yssel,
Martínez María Daniela,
ValdésPerez Calixto,
Ojalvo Ariana G,
Armstrong David G
Publication year - 2013
Publication title -
international wound journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.867
H-Index - 63
eISSN - 1742-481X
pISSN - 1742-4801
DOI - 10.1111/j.1742-481x.2012.12000.x
Subject(s) - medicine , downregulation and upregulation , pi3k/akt/mtor pathway , wound healing , cyclin d1 , cell cycle , cancer research , diabetic foot , diabetic foot ulcer , senescence , cyclin a , cell growth , microbiology and biotechnology , immunology , diabetes mellitus , endocrinology , biology , cancer , signal transduction , biochemistry , gene , genetics
Wound chronification and opportunistic infections stand as major factors leading to lower extremities amputations in diabetes. The molecular mechanisms underlying diabetic's torpid healing have not been elucidated. We present the case of a female diabetic patient that after a plantar abscess surgical drainage, tight glycaemia control and infection clearance; the wound bed evolved to chronification with poor matrix accumulation, scant angiogenesis and no evidence of dermo‐epidermal contours contraction. Ulcer fibroblasts yet cultured under ‘physiological’ conditions exhibited a slow and declining proliferative response. Diabetic fibroblasts cycle arrest occurred earlier than non‐diabetic counterparts. This in vitro premature arrest‐senescence phenotype appeared related to the transcriptional upregulation of p53 and the proto‐oncogene c‐myc; with a concomitant expression reduction of the survival and cellular growth promoters A kt and mTOR. Importantly, immunocytochemistry of the diabetic ulcer‐derived fibroblasts proved nuclear over expression of potent proliferation inhibitors and pro‐senescence proteins as p53 phosphorylated on serine‐15 and p21 Cip (1). In line with this, cyclin D1 appeared substantially underexpressed in these cells. We postulate that the downregulation of the A kt /mTOR/cyclin D1 axis by the proximal activation of p53 and p21 due to stressor factors, impose an arrest/pro‐senescence programme that translated in a torpid and slow healing process.