Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients

Lobmann, Ralf; Ambrosch, Andreas; Schultz, Gregory S.; Waldmann, K D; Schiweck, S.; Lehnert, Hendrik

doi:10.1007/s00125-002-0868-8

Cited by 509 publications

(397 citation statements)

References 48 publications

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“…It has been speculated that topical application of these agents, especially in the harsh microenvironment of a chronic wound, is fraught with problems. There are questions about the appropriate topical dose and the delivery vehicle, penetration of the polypeptide into the ulcer bed and its breakdown by tissue metalloproteinases (Robson et al, 1998;Trengove et al, 1999;Lobmann et al, 2002). Also, single growth factors may not be enough (Robson et al, 2000;Smith et al, 2000a,b).…”

Section: Discussionmentioning

confidence: 99%

“…In the case of venous ulcers, a number of hypotheses have been proposed. Some of these hypotheses have emphasized failure of the fibrinolytic system and the formation of pericapillary fibrin cuffs (Browse and Burnand, 1982;Van de Scheur and Falanga, 1997), while others have addressed the possibility of trapping of growth factors (Falanga and Eaglstein, 1993) and breakdown of extracellular matrix and cytokines by excessive amounts of tissue metalloproteinases (Trengove et al, 1999;Lobmann et al, 2002). More recently, however, a novel line of investigation has been centered on the hypothesis that chronic wounds fail to heal because their resident cells are senescent and/or have become unresponsive to the action of growth factors.…”

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confidence: 99%

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Fibroblasts from chronic wounds show altered TGF‐β‐signaling and decreased TGF‐β Type II Receptor expression

Kim

Park

et al. 2003

Journal Cellular Physiology

176

128

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Chronic wounds are characterized by failure to heal in a defined time frame. However, the pathogenic steps leading from the etiological factors to failure to heal are unknown. Recently, increasing evidence suggests that resident cells in chronic wounds display a number of critical abnormalities, including senescence and unresponsiveness to the stimulatory action of transforming growth factor-b1 (TGF-b1). In this study, we have determined some of the mechanisms that might be responsible for unresponsiveness to TGF-b1. Using Northern analysis and affinity labeling, we show that venous ulcer fibroblasts have decreased TGF-b Type II receptor expression. This finding is not the result of genetic mutation, as shown by experiments with Type II receptor satellite instability. Decreased Type II receptor expression was accompanied by failure of ulcer fibroblasts to phosphorylate Smad 2, Smad 3, and p42/44 mitogen activating protein kinase (MAPK), and was associated with a slower proliferative rate in response to TGF-b1. We conclude that venous ulcer fibroblasts show decreased Type II receptor expression and display abnormalities in the downstream signaling pathway involving MAPK and the early Smad pathway. These findings suggest ways to address and treat the abnormal cellular phenotype of cells in chronic wounds.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Fibroblasts from chronic wounds show altered TGF‐β‐signaling and decreased TGF‐β Type II Receptor expression

Kim

Park

et al. 2003

Journal Cellular Physiology

176

128

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“…Diabetes may influence foot wound healing in many ways, including an impairment of peripheral circulation, altered leucocyte function, disturbed balance of cytokines and proteases, and even chronic hyperglycaemia itself [78,79,80]. However, until recently, the role of offloading in impaired wound healing has not been considered [81].…”

Section: Wound Healing and The Importance Of Offloadingmentioning

confidence: 99%

“…Recent studies have also demonstrated other abnormalities frequently seen in chronic neuropathic diabetic foot ulcers. 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.…”

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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“…3 Decreased angiogenesis, 4 impaired growth factor production, 5 an altered inflammatory and immune response, 5 a decreased rate of wound contraction, 6 and an imbalance between the accumulation of extracellular components and their remodeling by matrix metalloproteinases (MMPs) 7,8 have all been demonstrated in diabetic wounds. MMP-2 and MMP-9 have been shown to be present in greater concentration in wounded diabetic animals than their nondiabetic littermates, which is similar to findings from patients with nonhealing ulcers.…”

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confidence: 99%

Impaired Biomechanical Properties of Diabetic Skin

Bermudez

Herdrich

et al. 2011

The American Journal of Pathology

106

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Diabetic skin is known to have deficient wound healing properties, but little is known of its intrinsic biomechanical properties. We hypothesize that diabetic skin possesses inferior biomechanical properties at baseline, rendering it more prone to injury. Skin from diabetic and nondiabetic mice and humans underwent biomechanical testing. Real-time PCR was performed for genes integral to collagen synthesis and degradation. MMP-2 and MMP-9, and TIMP-1 protein levels were assessed by ELISA and zymography. Collagen I and III content was assessed using Western blot analysis. At baseline, both murine and human diabetic skin was biomechanically inferior compared to nondiabetic skin, with decreased maximum stress and decreased modulus (P < 0.001 and < 0.05, respectively). Surprisingly, the expression of genes involved in collagen synthesis were significantly up-regulated, and genes involved in collagen degradation were significantly down-regulated in murine diabetic skin (P < 0.01). In addition, MMP-2 and MMP-9/TIMP-1 protein ratios were significantly lower in murine diabetic skin (P < 0.05). Collagen I levels and I:III ratios were lower in diabetic skin (P < 0.05). These findings suggest that the predisposition of diabetics to wounds may be the result of impaired tissue integrity at baseline, and are due, in part, to a defect in the regulation of collagen protein synthesis at the post-transcriptional level. Diabetes is associated with increased morbidity and mortality, 1 as well as impaired wound healing. 2 Diabetesrelated admissions accounted for 22% of all hospital inpatient days in 2007, and diabetic foot ulcers account for 20% of all hospital admissions in diabetic patients, which are the leading cause of lower extremity amputations. 2 Improvements made in diabetic wound management and prevention clearly have the potential to affect a large number of patients and decrease diabetic-related health care expenditures.More than 100 factors have been identified that contribute to the impairment in diabetic wound healing. 3 Decreased angiogenesis, 4 impaired growth factor production, 5 an altered inflammatory and immune response, 5 a decreased rate of wound contraction, 6 and an imbalance between the accumulation of extracellular components and their remodeling by matrix metalloproteinases (MMPs) 7,8 have all been demonstrated in diabetic wounds. MMP-2 and MMP-9 have been shown to be present in greater concentration in wounded diabetic animals than their nondiabetic littermates, which is similar to findings from patients with nonhealing ulcers. 9 Diabetes is characterized by significantly increased cross linking and nonenzymatic glycation of collagen, as well as elevated levels of advanced glycation end products (AGEs). 10,11 Blockade of the receptor for advanced glycation end products (RAGEs) can restore the wound healing properties of diabetic (Db/Db) mice. 12 Hyperglycemic animals have been shown to have significantly higher concentrations of glycated collagen and higher levels of collagenase activity. 9,13 Furthermore...

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Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients

Cited by 509 publications

References 48 publications

Fibroblasts from chronic wounds show altered TGF‐β‐signaling and decreased TGF‐β Type II Receptor expression

Fibroblasts from chronic wounds show altered TGF‐β‐signaling and decreased TGF‐β Type II Receptor expression

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

Impaired Biomechanical Properties of Diabetic Skin

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