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  • USA  (2)
  • glucocorticoid receptor  (2)
Keywords
  • 1
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; GROWTH ; CELL ; MODEL ; MODELS ; GENE ; transcription ; METABOLISM ; DIFFERENTIATION ; MICE ; ACTIVATION ; DNA ; MECHANISM ; MARKER ; primary ; INDUCTION ; KERATINOCYTES ; mechanisms ; SKIN ; MATURATION ; MOUSE ; NUMBER ; DNA-BINDING ; SIGNALING PATHWAY ; epidermis ; ARCHITECTURE ; desmosomes ; USA ; LOSSES ; HOMEOSTASIS ; BARRIER ; CASPASE-14 ; EPIDERMAL-KERATINOCYTES ; FETAL MOUSE
    Abstract: To investigate the contribution of the glucocorticoid receptor (GR) in skin development and the mechanisms underlying this function, we have analyzed two mouse models in which GR has been functionally inactivated: the knockout GR(-/-) mice and the dimerization mutant GR(dim/dim) that mediates defective DNA binding-dependent transcription. Because GR null mice die perinatally, we evaluated skin architecture of late embryos by histological, immunohistochemical, and electron microscopy studies. Loss of function of GR resulted in incomplete epidermal stratification with dramatically abnormal differentiation of GR(-/-), but not GR(+/-) embryos, as demonstrated by the lack of loricrin, filaggrin, and involucrin markers. Skin sections of GR(-/-) embryos revealed edematous basal and lower spinous cells, and electron micrographs showed increased intercellular spaces between keratinocytes and reduced number of desmosomes. The absent terminal differentiation in GR(-/-) embryos correlated with an impaired activation of caspase-14, which is required for the processing of profilaggrin into filaggrin at late embryo stages. Accordingly, the skin barrier competence was severely compromised in GR(-/-) embryos. Cultured mouse primary keratinocytes from GR(-/-) mice formed colonies with cells of heterogeneous size and morphology that showed increased growth and apoptosis, indicating that GR regulates these processes in a cell-autonomous manner. The activity of ERK1/2 was constitutively augmented in GR(-/-) skin and mouse primary keratinocytes relative to wild type, which suggests that GR modulates skin homeostasis, at least partially, by antagonizing ERK function. Moreover, the epidermis of GR(+/dim) and GR(dim/dim) embryos appeared normal, thus suggesting that DNA-binding-independent actions of GR are sufficient to mediate epidermal and hair follicle development during embryogenesis
    Type of Publication: Journal article published
    PubMed ID: 18039792
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  • 2
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; VITRO ; DISEASE ; MICE ; TIME ; MACROPHAGES ; SERA ; REDUCTION ; animals ; bone marrow ; BONE-MARROW ; DELETION ; NO ; LESIONS ; DIFFERENCE ; inactivation ; MUSCLE ; ATHEROSCLEROSIS ; DIET ; MOUSE MODEL ; VASCULATURE ; glucocorticoid receptor ; CALCIUM ; BEHAVIOR ; SMOOTH-MUSCLE ; inflammation ; SERUM ; PRODUCTS ; INCREASE ; DEFICIENT MICE ; GC ; methods ; dexamethasone ; USA ; BONE ; animal ; SMOOTH-MUSCLE-CELLS ; smooth muscle cells ; MEDIA ; RANKL ; VASCULAR CALCIFICATION ; MUSCLE-CELLS ; MARROW ; in vitro ; CRUCIAL ROLE ; DRIVEN ; ARTERIAL CALCIFICATION ; CHOLESTEROL-FED RABBITS ; CORONARY ANGIOPLASTY ; KAPPA-B LIGAND ; OSTEOPROTEGERIN ; RECEPTOR ACTIVATOR
    Abstract: Objective - Macrophage-derived products are known to play a crucial role during atherogenesis and vascular calcification. Glucocorticoids (GC) are important modulators of immune cell functions, but their specific effects on macrophages behavior during plaque formation are not defined. The present study was therefore designed to investigate the effects of macrophage-specific deletion of the glucocorticoid receptor (GR(LysMCre)) on atherogenesis and vascular calcification in a hyperlipidemic mouse-model. Methods and Results - Bone marrow was isolated from GRLysMCre mice and wild-type controls (GR(flox)) and subsequently transplanted into lethally irradiated LDL-receptor -deficient mice. Animals were fed a Western-type diet for 15 or 24 weeks, and atherosclerotic lesions within the aortic sinus were evaluated. At both time points, no significant difference in serum lipid and corticosterone concentrations, atherosclerotic lesion size and macrophage-content within the lesions could be observed. However, GRLysMCre mice showed less calcification as well as a significant reduction of RANKL, BMP2, and Msx2 expression within the vasculature. In vitro studies using conditioned media from macrophages which had been stimulated with dexamethasone demonstrated a dose-dependent increase in calcium deposition by vascular smooth muscle cells. Conclusion - This study demonstrates that macrophage-specific glucocorticoid receptor inactivation reduces vascular calcification without affecting atherosclerotic lesion size in LDL receptor -deficient mice. (Arterioscler Thromb Vasc Biol. 2008;28:2158-2164.)
    Type of Publication: Journal article published
    PubMed ID: 18787189
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  • 3
    Keywords: CELLS ; GROWTH-FACTOR ; glucocorticoid receptor ; ESTROGEN-RECEPTOR ; L-ARGININE ; SURVIVAL SIGNALS ; HIGH-DOSE METHYLPREDNISOLONE ; SPINAL-CORD INJURY ; INFARCT VOLUME ; KINASE SGK
    Abstract: Many cellular responses to corticosteroids involve the transcriptional modulation of target genes by the glucocorticoid receptor (GR). A rapid, non-nuclear effect of GR was found to mediate neuroprotection. High-dose corticosteroids (20 mg/kg intraperitoneally), given within 2 hours of transient cerebral ischemia, acutely increased endothelial nitric oxide synthase (eNOS) activity, augmented regional cerebral blood flow (CBF) by 40% to 50%, and reduced cerebral infarct size by 32%. These neuroprotective effects of corticosteroids were abolished by the GR antagonist RU486 and by inhibition of phosphatidylinositol 3-kinase (PI3K), and were absent in eNOS(-/-) mice. To determine the mechanism by which GR activated eNOS, we measured the effect of corticosteroids on PI3K and the protein kinase Akt. In a ligand-dependent manner, GR activated PI3K and Akt in vitro and in vivo caused NO-dependent vasodilation, which was blocked by cotreatment with RU486 or the PI3K inhibitor LY294002 but not by transcriptional inhibitors. Indeed, a mutant GR, which cannot dimerize and bind to DNA, still activated PI3K and Akt in response to corticosteroids. These findings indicate that non-nuclear GR rapidly activates eNOS through the PI3K/Akt pathway and suggest that this mechanism mediates the acute neuroprotective effects of corticosteroids through augmentation of CBF.
    Type of Publication: Journal article published
    PubMed ID: 12464678
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