Abnormal Connexin Expression Underlies Delayed Wound Healing in Diabetic Skin

Published on Nov 1, 2007in Diabetes9.461
· DOI :10.2337/DB07-0613
Chiuhui Mary Wang4
Estimated H-index: 4
(UCL: University College London),
Jill Lincoln1
Estimated H-index: 1
+ 1 AuthorsDavid L. Becker51
Estimated H-index: 51
Sources
Abstract
OBJECTIVE— Dynamically regulated expression of the gap junction protein connexin (Cx)43 plays pivotal roles in wound healing. Cx43 is normally downregulated and Cx26 upregulated in keratinocytes at the edge of the wound as they adopt a migratory phenotype. We have examined the dynamics of Cx expression during wound healing in diabetic rats, which is known to be slow. RESEARCH DESIGN AND METHODS— We induced diabetes with streptozotocin and examined Cx expression and communication in intact and healing skin. RESULTS— We found that diabetes decreased Cx43 and Cx26 protein and communication in the intact epidermis and increased Cx43 protein and communication in the intact dermis. Diabetes also altered the dynamic changes of Cxs associated with wound healing. Within 24 h, Cx43 was upregulated in a thickened bulb of keratinocytes at the wound edge (rather than downregulated as in controls, which formed a thin process of migratory cells). Cx43 decline was delayed until 48 h, when reepithelialization began. Although Cx26 was upregulated as normal after wounding in diabetic skin, its distribution at the wound edge was abnormal, being more widespread. Application of Cx43-specific antisense gel to diabetic wounds prevented the abnormal upregulation of Cx43 and doubled the rate of reepithelialization, which exceeded control levels. CONCLUSIONS— Cx expression in diabetic skin is abnormal, as is the dynamic response of Cx43 to injury, which may underlie the delayed healing of diabetic wounds. Preventing the upregulation of Cx43 in diabetic wounds significantly improves the rate of healing and clearly has potential therapeutic value.
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#1Ryoichi Mori (UoB: University of Bristol)H-Index: 5
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Experimental downregulation of connexin43 (Cx43) expression at skin wound sites appears to markedly improve the rate and quality of healing, but the underlying mechanisms are currently unknown. Here, we have compared physiological and cell biological aspects of the repair process with and without Cx43 antisense oligodeoxynucleotide treatment. Treated wounds exhibited accelerated skin healing with significantly increased keratinocyte and fibroblast proliferation and migration. In vitro knockdown ...
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Urinary bladder dysfunction is a major complication in diabetes mellitus and its mechanism has been attributed to altered neurological function (autonomic and/or peripheral neuropathy). Previous studies have demonstrated impaired nerve deficiencies, including either loss of nerve function and/or anatomical loss of neuromuscular nerve terminals. While the phenomenon of diabetes-related neurological injury is well recognised, its pathogenesis is not well understood. Using a well established rat mo...
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#1Jianhong Zhang (ANU: Australian National University)H-Index: 2
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Differential connexin expression in preglomerular and postglomerular vasculature: Accentuation during diabetes. Background Gap junctions may play an important role in regulating renal blood flow and glomerular responses. We have therefore made a comprehensive analysis of connexin expression in the renal vasculature of control and diabetic mice since elevated glucose has been reported to down-regulate connexin 43 in vascular cells in vitro. Methods Connexin distribution was determined with immuno...
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Summary Extension of a burn wound over the first 24h following injury is recognised clinically, and leads to diagnostic and therapeutic dilemmas. In the central nervous system, a similar spread of damage, beyond the initial injury, can occur via the spread of death signals from injured cells to their healthy neighbours via Connexin43 (Cx43) gap junction channels. In the skin, Cx43 is expressed in the basal epidermis and in fibroblasts and dermal appendages. We have used Cx43 specific antisense o...
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#1Dale W. Laird (UWO: University of Western Ontario)H-Index: 71
Gap junction proteins, connexins, are dynamic polytopic membrane proteins that exhibit unprecedented short half-lives of only a few hours. Consequently, it is well accepted that in addition to channel gating, gap junctional intercellular communication is regulated by connexin biosynthesis, transport and assembly as well as the formation and removal of gap junctions from the cell surface. At least nine members of the 20-member connexin family are known to be phosphorylated en route or during thei...
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▪ Abstract Gap junctions contain hydrophilic membrane channels that allow direct communication between neighboring cells through the diffusion of ions, metabolites, and small cell signaling molecules. They are made up of a hexameric array of polypeptides encoded by the connexin multi-gene family. Cell-cell communication mediated by connexins is crucial to various cellular functions, including the regulation of cell growth, differentiation, and development. Mutations in connexin genes have been l...
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In this issue, Brandner et al have extended previous observations on changes in connexin distribution during skin wound healing and have also proposed that keratinocytes grafted into a wound bed might help to reconstitute a tissue gap junction network dominated by connexins 26 and 30 (hyperproliferative connexins). These findings alert us to the possibility that targeting of specific connexins could provide a new approach to improving therapy of acute and chronic skin wounds.
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The repair of tissue damage is a key survival process in all organisms and involves the coordinated activation of several cell types. Cell-cell communication is clearly fundamental to this process, and a great deal is known about extracellular communication within the wound site via cytokines [1, 2]. Here we show that direct cell-cell communication through connexin 43 (Cx43) gap junction channels [3, 4] also plays a major role in the wound healing process. In two different wound healing models, ...
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