Topically applied connective tissue growth factor/CCN2 improves diabetic preclinical cutaneous wound healing: potential role for CTGF in human diabetic foot ulcer healing.

F R Henshaw,L Lo,S M Twigg,P Boughton,S V Mclennan

doi:10.1155/2015/236238

F R Henshaw, L Lo + Show 3 more

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https://doi.org/10.1155/2015/236238

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Abstract

Aims/Hypothesis. Topical application of CTGF/CCN2 to rodent diabetic and control wounds was examined. In parallel research, correlation of CTGF wound fluid levels with healing rate in human diabetic foot ulcers was undertaken. Methods. Full thickness cutaneous wounds in diabetic and nondiabetic control rats were treated topically with 1 μg rhCTGF or vehicle alone, on 2 consecutive days. Wound healing rate was observed on day 14 and wound sites were examined for breaking strength and granulation tissue. In the human study across 32 subjects, serial CTGF regulation was analyzed longitudinally in postdebridement diabetic wound fluid. Results. CTGF treated diabetic wounds had an accelerated closure rate compared with vehicle treated diabetic wounds. Healed skin withstood more strain before breaking in CTGF treated rat wounds. Granulation tissue from CTGF treatment in diabetic wounds showed collagen IV accumulation compared with nondiabetic animals. Wound α-smooth muscle actin was increased in CTGF treated diabetic wounds compared with untreated diabetic wounds, as was macrophage infiltration. Endogenous wound fluid CTGF protein rate of increase in human diabetic foot ulcers correlated positively with foot ulcer healing rate (r = 0.406; P < 0.001). Conclusions/Interpretation. These data collectively increasingly substantiate a functional role for CTGF in human diabetic foot ulcers.

Highlights

Foot ulceration secondary to diabetes occurs in up to onequarter of people with diabetes [1] and is the commonest cause of lower limb amputation, accounting for 50–70% of nontraumatic cases [2]
Pathogenic factors lead to suboptimal extracellular matrix (ECM) composition: it has been hypothesized that a cytokine/chemokine mediated imbalance between synthetic and degradative matrix pathways is responsible for the reduced amount and quality of ECM [7]
In contrast to Connective Tissue Growth Factor (CTGF) effects in diabetic wounds, nondiabetic wounds treated with CTGF (C + CTGF) did not show improved closure rates relative to controls alone (C + phosphate buffered saline (PBS))

Summary

Introduction

Foot ulceration secondary to diabetes occurs in up to onequarter of people with diabetes [1] and is the commonest cause of lower limb amputation, accounting for 50–70% of nontraumatic cases [2]. Wounds in diabetic patients typically show abnormal healing, characterized by chronicity, persistent inflammation, copious exudate, hypergranulation, increased bacterial load, and reduced ability to heal [6]. This delayed healing is thought to be due to a combination of factors including macro- and microvascular disease, neuropathy, bacterial infection, local pressure due to foot deformity, and the adverse local metabolic environment caused by diabetes. Human diabetic wounds exhibit an excess of proinflammatory cytokines such as TNF-α, which contribute to an environment of increased protease activity in diabetic wounds [7]

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