Lack of insulin-like growth factor 1 (IGF1) in the basal keratinocyte layer of diabetic skin and diabetic foot ulcers

Blakytny, Robert; Jude, Edward B.; Gibson, J. M.; Boulton, Andrew J.M.; Ferguson, Mark W. J.

doi:10.1002/(sici)1096-9896(200004)190:5<589::aid-path553>3.0.co;2-t

Cited by 140 publications

(99 citation statements)

References 24 publications

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“…Igf1 is induced in wounds, both in animals (57,58) and humans (59,60), but is missing in chronic wounds (61). Pro liferation and migration of keratinocytes and fibroblasts is promoted by Igf1 in vitro (62,63) and, interestingly, its levels are reduced in cells isolated from diabetic foot ulcers (64) and in diabetic mouse wounds (65). Igf1 treatment or overexpression has been shown to promote wound healing in diabetic ani mals (66,67).…”

Section: Resultsmentioning

confidence: 99%

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Bhattacharya

Aggarwal

Singh

et al. 2015

Mol Med

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Delayed wound healing is a major complication associated with diabetes and is a result of a complex interplay among diverse deregulated cellular parameters. Although several genes and pathways have been identified to be mediating impaired wound closure, the role of microRNAs (miRNAs) in these events is not very well understood. Here, we identify an altered miRNA signature in the prolonged inflammatory phase in a wound during diabetes, with increased infiltration of inflammatory cells in the basal layer of the epidermis. Nineteen miRNAs were downregulated in diabetic rat wounds (as compared with normal rat wound, d 7 postwounding) together with inhibited levels of the central miRNA biosynthesis enzyme, Dicer, suggesting that in wounds of diabetic rats, the decreased levels of Dicer are presumably responsible for miRNA downregulation. Compared with unwounded skin, Dicer levels were significantly upregulated 12 d postwounding in normal rats, and this result was notably absent in diabetic rats that showed impaired wound closure. In a wound-healing specific quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) array, 10 genes were significantly altered in the diabetic rat wound and included growth factors and collagens. Network analyses demonstrated significant interactions and correlations between the miRNA predicted targets (regulators) and the 10 wound-healing specific genes, suggesting altered miRNAs might fine-tune the levels of these genes that determine wound closure. Dicer inhibition prevented HaCaT cell migration and affected wound closure. Altered levels of Dicer and miRNAs are critical during delayed wound closure and offer promising targets to address the issue of impaired wound healing.

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Section: Resultsmentioning

confidence: 99%

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Bhattacharya

Aggarwal

Singh

et al. 2015

Mol Med

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“…46 Conversely, compromised wound healing has been associated with deregulation of IGF-1 signaling. 12,13 Similar to wound healing, hair growth and regeneration involve proliferation, migration, and differentiation of keratinocytes. It has also been associated with IGF-1 action 57 because mice carrying a null mutation in the Igf-1r gene exhibited reduced number and size of the hair follicles.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of mIGF-1 in Keratinocytes Improves Wound Healing and Accelerates Hair Follicle Formation and Cycling in Mice

Semenova

Koegel

Hasse

et al. 2008

The American Journal of Pathology

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Insulin-like growth factor 1 (IGF-1) is an important regulator of growth, survival, and differentiation in many tissues. It is produced in several isoforms that differ in their N-terminal signal peptide and C-terminal extension peptide. The locally acting isoform of IGF-1 (mIGF-1) was previously shown to enhance the regeneration of both muscle and heart. In this study, we tested the therapeutic potential of mIGF-1 in the skin by generating a transgenic mouse model in which mIGF-1 expression is driven by the keratin 14 promoter. IGF-1 levels were unchanged in the sera of hemizygous K14/mIGF-1 transgenic animals whose growth was unaffected. A skin analysis of young animals revealed normal architecture and thickness as well as proper expression of differentiation and proliferation markers. No malignant tumors were formed. Normal homeostasis of the putative stem cell compartment was also maintained. Healing of full-thickness excisional wounds was accelerated because of increased proliferation and migration of keratinocytes, whereas inflammation, granulation tissue formation, and scarring were not obviously affected. In addition, mIGF-1 promoted late hair follicle morphogenesis and cycling. To our knowledge, this is the first work to characterize the simultaneous, stimulatory effect of IGF-1 delivery to keratinocytes on two types of regeneration processes within a single mouse model. Our analysis supports the use of mIGF-1 for skin and hair regeneration and describes a potential cell type-restricted action. (Am J

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“…Jude et al described the lack of up-regulation of TGF-β1 in foot ulcers, and Lobmann and colleagues described increases in matrix metalloproteinases and decreased concentration of their inhibitors, both of which could explain impaired wound healing [79,80]. A lack of insulin-like growth factor-1 in the basal keratinocyte layer of biopsies from foot ulcers [93], and increased nitric oxide synthase activity in foot ulcers [94] may also be contributory to retarded wound healing in diabetes. Recent studies suggest that psychological distress (depression and anxiety) is common in diabetic patients with neuropathy and foot ulcers [38].…”

Section: Wound Healing and The Importance Of Offloadingmentioning

confidence: 99%

The diabetic foot: from art to science. The 18th Camillo Golgi lecture

2004

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Diabetic foot ulceration represents a major medical, social and economic problem all over the world. While more than 5% of diabetic patients have a history of foot ulceration, the cumulative lifetime incidence may be as high as 15%. Ethnic differences exist in both ulcer and amputation incidences, with both being less common in patients of Indian subcontinent origin living in the UK. Foot ulceration results from the interaction of several contributory factors, the most important of which is neuropathy. With respect to the management of acute Charcot neuroarthropathy in diabetes, recent studies suggest that bisphosphonates reduce disease activity as judged not only by differences in skin temperature, but also by assessing markers of bone turnover. The use of the total-contact cast is demonstrated in the treatment of acute Charcot feet and of plantar neuropathic ulcers. Histological evidence suggests that pressure relief results in chronic foot ulcers changing their morphological appearance by displaying some features of an acute wound. Thus, repetitive stresses on the insensate foot appear to play a major role in maintaining ulcer chronicity. It is hoped that increasing research activity in foot disease will ultimately result in fewer ulcers and less amputation in diabetes.

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Lack of insulin-like growth factor 1 (IGF1) in the basal keratinocyte layer of diabetic skin and diabetic foot ulcers

Cited by 140 publications

References 24 publications

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

Overexpression of mIGF-1 in Keratinocytes Improves Wound Healing and Accelerates Hair Follicle Formation and Cycling in Mice

The diabetic foot: from art to science. The 18th Camillo Golgi lecture

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