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ABSTRACT: Following a skin injury, the damaged tissue is repaired through the coordinated biological actions that constitute the cutaneous healing response. In mammals, repaired skin is not identical to intact uninjured skin, however, and this disparity may be caused by differences in the mechanisms that regulate postnatal cutaneous wound repair compared to embryonic skin development. Improving our understanding of the molecular pathways that are involved in these processes is essential to generate new therapies for wound healing complications. Here we focus on the roles of several key developmental signaling pathways (Wnt/β-catenin, TGF-β, Hedgehog, Notch) in mammalian cutaneous wound repair, and compare this to their function in skin development. We discuss the varying responses to cutaneous injury across the taxa, ranging from complete regeneration to scar tissue formation. Finally, we outline how research into the role of developmental pathways during skin repair has contributed to current wound therapies, and holds potential for the development of more effective treatments.
Cellular and Molecular Life Sciences CMLS 10/2012; · 6.57 Impact Factor
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ABSTRACT: β-Catenin is an important regulator of dermal fibroblasts during cutaneous wound repair. However, the factors that modulate β-catenin activity in this process are not completely understood. We investigated the role of the extracellular matrix in regulating β-catenin and found an increase in β-catenin-mediated Tcf-dependent transcriptional activity in fibroblasts exposed to various extracellular matrix components. This occurs through an integrin-mediated GSK3β-dependent pathway. The physiologic role of this mechanism was demonstrated during wound repair in extra domain A-fibronectin-deficient mice, which exhibited decreased β-catenin-mediated signaling during the proliferative phase of healing. Extra domain A-fibronectin-deficient mice have wounds that fail at a lower tensile strength and contain fewer fibroblasts compared with wild type mice. This phenotype was rescued by genetic or pharmacologic activation of β-catenin signaling. Because fibronectin is a transcriptional target of β-catenin, this suggests the existence of a feedback loop between these two molecules that regulates dermal fibroblast cell behavior during wound repair.
Journal of Biological Chemistry 06/2011; 286(31):27687-97. · 4.77 Impact Factor
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ABSTRACT: β-catenin is an important regulator of dermal fibroblasts during cutaneous wound repair. However, the factors that modulate
β-catenin activity in this process are not completely understood. We investigated the role of the extracellular matrix in
regulating β-catenin and found an increase in β-catenin mediated Tcf dependent transcriptional activity in fibroblasts exposed
to various extracellular matrix components. This occurs through an integrin-mediated GSK3β-dependent pathway. The physiologic
role of this mechanism was demonstrated during wound repair in EDA-fibronectin deficient mice, which exhibited decreased β-catenin-mediated
signaling during the proliferative phase of healing. EDA-fibronectin deficient mice have wounds which fail at a lower tensile
strength and contain fewer fibroblasts compared to wild type mice. This phenotype was rescued by genetic or pharmacologic
activation of β-catenin signaling. Since fibronectin is a transcriptional target of β-catenin, this suggests the existence
of a feedback loop between these two molecules that regulates dermal fibroblast cell behavior during wound repair.
Journal of Biological Chemistry 06/2011; · 4.77 Impact Factor
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ABSTRACT: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates most biological responses to 2,3, 7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related aromatic hydrocarbons. Although the role of the AHR in control of drug metabolism and endocrine disruption is partly understood, we know little about the regulation of the AHR itself by endocrine factors. Our work with hypophysectomized rats suggested that hepatic AHR protein level is positively regulated by pituitary-dependent factors. A current hypothesis is that adrenal glucocorticoids elevate AHR expression and enhance responsiveness to AHR agonists. Dexamethasone (DEX) at concentrations that activate the glucocorticoid receptor (GR) increased AHR mRNA, protein, and TCDD-binding by approximately 50% in Hepa-1 mouse hepatoma cells. This response was blocked by the GR antagonist 17beta-hydroxy-11beta-[4-dimethylamino phenyl]-17alpha-[1-propynyl]estra-4,9-dien-3-one (RU486), suggesting GR involvement. This small magnitude increase in AHR levels was functionally significant; pretreatment of Hepa-1 cells with DEX caused a 75% increase in the maximum induction of an AHR-activated luciferase reporter plasmid by TCDD. A luciferase reporter under control of the proximal 2.5 kilobases of the mouse Ahr 5'-flanking region and promoter was induced approximately 2.5-fold by DEX when cotransfected with a mouse GR expression plasmid. This is the first demonstration that glucocorticoids increase AHR levels in hepatoma cells via a GR-dependent transcriptional mechanism, suggesting a novel aspect of cross-talk between the AHR and the GR.
Drug metabolism and disposition: the biological fate of chemicals 04/2008; 36(3):543-51. · 3.74 Impact Factor
