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  • DIFFERENTIATION  (2)
  • 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: CELLS ; proliferation ; DIFFERENTIATION ; HEALTH ; BONE-FORMATION ; OSTEOPOROSIS ; POSTMENOPAUSAL WOMEN ; RANDOMIZED CONTROLLED-TRIAL ; RECEPTOR-ALPHA ; CANCELLOUS BONE
    Abstract: Postmenopausal osteoporosis is characterized by declining estrogen levels, and estrogen replacement therapy has been proven beneficial for preventing bone loss in affected women. While the physiological functions of estrogen in bone, primarily the inhibition of bone resorption, have been studied extensively, the effects of pharmacological estrogen administration are still poorly characterized. Since elevated levels of follicle-stimulating hormone (FSH) have been suggested to be involved in postmenopausal bone loss, we investigated whether the skeletal response to pharmacological estrogen administration is mediated in a FSH-dependent manner. Therefore, we treated wildtype and FSHbeta-deficicent (Fshb(-/-)) mice with estrogen for 4 weeks and subsequently analyzed their skeletal phenotype. Here we observed that estrogen treatment resulted in a significant increase of trabecular and cortical bone mass in both, wildtype and Fshb(-/-) mice. Unexpectedly, this FSH-independent pharmacological effect of estrogen was not caused by influencing bone resorption, but primarily by increasing bone formation. To understand the cellular and molecular nature of this osteo-anabolic effect we next administered estrogen to mouse models carrying cell specific mutant alleles of the estrogen receptor alpha (ERalpha). Here we found that the response to pharmacological estrogen administration was not affected by ERalpha inactivation in osteoclasts, while it was blunted in mice lacking the ERalpha in osteoblasts or in mice carrying a mutant ERalpha incapable of DNA binding. Taken together, our findings reveal a previously unknown osteo-anabolic effect of pharmacological estrogen administration, which is independent of FSH and requires DNA-binding of ERalpha in osteoblasts.
    Type of Publication: Journal article published
    PubMed ID: 23209701
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