A role for endogenous glucocorticoids in wound repair

Grose, Richard; Werner, S.; Kessler, Daniela; Tuckermann, Jan; Huggel, Katharina; Durka, Silke; Reichardt, Holger M.; Werner, Sabine

doi:10.1093/embo-reports/kvf119

Cited by 58 publications

(44 citation statements)

References 15 publications

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“…Steroids potently suppress the local and systemic inflammatory response in GR dim mice, and repression of AP-1 and NF-κB-dependent genes, such as matrix metalloproteinase-3 and collagenase-3, is comparable to wild-type mice [48,49,50]. Indeed, analysis of GR dim mice has recently provided insight into the mechanism of impaired wound repair [51]. After skin injury there is enhanced granulation tissue and increased numbers of fibroblasts in GR dim mice as compared to control, suggesting that the inhibitory effect of steroids on wound healing is mediated by the DNA binding activity of GR (see Table 1).…”

Section: Transcriptional Modulation By Gr: Dna Binding Vs Protein-prmentioning

confidence: 99%

Nontranscriptional actions of the glucocorticoid receptor

Limbourg

Liao

2003

J Mol Med

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Many cellular responses to corticosteroids involve the transcriptional modulation of target genes by a prototypical nuclear receptor, the glucocorticoid receptor (GR). In the classic model of steroid hormone action GR acts as ligand-dependent transcription factor by either activating or repressing gene expression through direct interactions with DNA or other transcription factors. Recent evidence suggests an important role for nontranscriptional effects of GR in the vascular system. The nontranscriptional actions of GR involve the rapid activation of protein kinases, such as phosphatidylinositol-3 kinase and Akt, leading to the activation of endothelial nitric oxide synthase. This novel pathway of steroid hormone action protects against ischemic injury by augmenting blood flow and decreasing vascular inflammation.

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Section: Transcriptional Modulation By Gr: Dna Binding Vs Protein-prmentioning

confidence: 99%

Nontranscriptional actions of the glucocorticoid receptor

Limbourg

Liao

2003

J Mol Med

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“…Effective cell-matrix communication is crucial for efficient wound healing. Several nuclear hormone receptors, one of the largest known classes of transcription factors, have been implicated wound repair (8,9). Of interest, studies have shown that nuclear hormone receptor peroxisome proliferator-activated receptor ␤/␦ (PPAR␤/␦) is an early transcription factor that modulates keratinocyte response to inflammation during wound healing (10,11).…”

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confidence: 99%

Angiopoietin-like 4 Interacts with Matrix Proteins to Modulate Wound Healing*

Goh

Pal

Chong

et al. 2010

Journal of Biological Chemistry

132

153

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A dynamic cell-matrix interaction is crucial for a rapid cellular response to changes in the environment. Appropriate cell behavior in response to the changing wound environment is required for efficient wound closure. However, the way in which wound keratinocytes modify the wound environment to coordinate with such cellular responses remains less studied. We demonstrated that angiopoietin-like 4 (ANGPTL4) produced by wound keratinocytes coordinates cell-matrix communication. ANGPTL4 interacts with vitronectin and fibronectin in the wound bed, delaying their proteolytic degradation by metalloproteinases. This interaction does not interfere with integrinmatrix protein recognition and directly affects cell-matrix communication by altering the availability of intact matrix proteins. These interactions stimulate integrin-focal adhesion kinase, 14-3-3, and PKC-mediated signaling pathways essential for effective wound healing. The deficiency of ANGPTL4 in mice delays wound re-epithelialization. Further analysis revealed that cell migration was impaired in the ANGPTL4-deficient keratinocytes. Altogether, the findings provide molecular insight into a novel control of wound healing via ANGPTL4-dependent regulation of cell-matrix communication. Given the known role of ANGPTL4 in glucose and lipid homeostasis, it is a prime therapeutic candidate for the treatment of diabetic wounds. It also underscores the importance of cell-matrix communication during angiogenesis and cancer metastasis.Skin repair after an injury proceeds via a finely tuned pattern of integrated biological events aimed at restoration of the epithelial barrier. The inflammatory stage of repair is followed by the proliferation and migration of keratinocytes, a process called re-epithelialization (1). These events are regulated spatiotemporally by several classical growth factors and cytokines, the effects of which have been well documented (2). Less studied are extracellular factors such as matricellular proteins and adipocytokines, both shown to have a profound local impact during wound repair (3, 4). Effective directed cell migration requires constant cellular interaction with the extracellular matrix (ECM) 3 in response to the changing wound environment. Although the importance of such cell-matrix communication in wound healing is well recognized, the mechanism that modifies the external wound microenvironment for coordinated keratinocyte behavior remains unclear.Integrins on the cell surface often function as biosensors to constantly interrogate the wound environment and modulate cell responses accordingly. Binding of integrins to their cognate matrix proteins activates intracellular signaling pathways that modulate a broad range of cellular processes, including cell migration (5). Integrin-mediated signaling requires that integrins bind substrate-anchored matrix proteins. This interaction provides mechanical resistance that permits tensional forces to be generated via the actomyosin system (6). In contrast, small soluble matrix protein fragments gene...

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“…However, when the analysis of GR dim mice was expanded to other inflammatory processes, we observed a failure of GCs to exert a full anti-inflammatory response. This was the case for exogenous actions of GCs in contact allergy and for the modulatory role of endogenous GCs in septic shock and for the early response during wound healing exhibiting elevated cytokine and chemokine expression (Grose et al, 2002;Tuckermann et al, 2007). As a side effect GC inhibition of bone formation occur in these mice.…”

Section: Resultsmentioning

confidence: 99%

“…) Wound healing like in wild type; but delayed kinetik (Grose et al, 2002) Hepatic GH activity controlling body growth like in wild type A c c e p t e d M a n u s c r i p t…”

Section: Phenotypes Of Pharmacological Gc Administration In Gr Dim Micementioning

confidence: 99%

“…Phenotype Beneficial Effects of GC Treatment of irritant dermatitis like in wild type (Reichardt et al, 2001) Treatment of CHS impaired (Tuckermann et al, 2007) Suppression of inflammatory mediators like in wild type: TNFa (Tuckermann et al, 2007), MMP-13, MMP-9 (Tuckermann et al, 1999) impaired : MCP-1, IP-10, IL-1b (Grose et al, 2002;Tuckermann et al, 2007) PI3K coactivation by high dose GC, important for stero id protection from stroke like in wild type: PI3K activity normal in GR dim MEFs (Limbourg et al, 2002) …”

Section: Phenotypes Of Pharmacological Gc Administration In Gr Dim Micementioning

confidence: 99%

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Glucocorticoid receptor action in beneficial and side effects of steroid therapy: Lessons from conditional knockout mice

Kleiman

Tuckermann

2007

Molecular and Cellular Endocrinology

146

122

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Tuckermann. Glucocorticoid receptor action in beneficial and side effects of steroid therapy: Lessons from conditional knockout mice. Molecular and Cellular Endocrinology, Elsevier, 2007, 275 (1-2) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. dimerization-deficient GR demonstrate that some inflammatory processes can be suppressed by GCs, while others can not. Also side effects of GCs occur in these mice. Thus, depending on the process that is treated, SEGRA could be therapeutically more or less effective and not all side effects of steroid therapy may be reduced.

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A role for endogenous glucocorticoids in wound repair

Cited by 58 publications

References 15 publications

Nontranscriptional actions of the glucocorticoid receptor

Nontranscriptional actions of the glucocorticoid receptor

Angiopoietin-like 4 Interacts with Matrix Proteins to Modulate Wound Healing*

Glucocorticoid receptor action in beneficial and side effects of steroid therapy: Lessons from conditional knockout mice

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