A Krust

Collège de France, Lutetia Parisorum, Île-de-France, France

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Publications (56)408.71 Total impact

  • Annales d Endocrinologie 09/2012; 73(4):254. DOI:10.1016/j.ando.2012.07.074 · 0.66 Impact Factor
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    ABSTRACT: Introduction Les œstrogènes préviennent l’accumulation de masse grasse et l’installation d’une insulinorésistance via leur récepteur α (ERα). Ce récepteur nucléaire est connu pour réguler la transcription de nombreux gènes grâce à deux fonctions de transactivation, AF-1 et AF-2, et nous avons récemment montré que, en activant le récepteur indépendamment de la fonction AF-1, il est possible de conserver l’intégralité des effets protecteurs des œstrogènes sur le métabolisme glucidique et la paroi vasculaire, sans effet délétère sur l’utérus. Matériels et méthodes Pour déterminer l’implication de la fonction AF-2 dans l’action bénéfique des œstrogènes sur la composition corporelle, la sensibilité à l’insuline et l’homéostasie glucidique, des souris déficientes en ERα (ERα−/−) ou spécifiquement en AF-2 (AF-2°), ont été étudiées en conditions de régime standard ou hyperlipidique (mâles et femelles, n = 8–10 par sexe et par génotype). Résultats Par comparaison à leurs contrôles sauvages, les souris ERα−/− et AF-2° sont caractérisées par une prise de poids accélérée avec accumulation massive de tissu adipeux, une insulinorésistance et une intolérance au glucose. Pour s’affranchir de l’effet potentiel des stéroïdes sexuels endogènes, des souris femelles ovariectomisées ont ensuite reçu une administration chronique de 17β- estradiol à doses physiologiques. Comme attendu, ce traitement prévient l’excès d’adiposité, ainsi que l’altération de la sensibilité à l’insuline (clamps hyperinsulinémiques, voie de signalisation de l’insuline dans les tissus périphériques) et de la tolérance au glucose chez les souris sauvages, mais ces effets sont totalement abolis chez les souris ERα−/− et AF-2°. Conclusion Comme précédemment démontré concernant leurs effets vasculoprotecteurs, l’action bénéfique des œstrogènes sur l’adiposité, la sensibilité à l’insuline et la tolérance au glucose s’avère indépendante de la fonction AF-1, mais dépendante de la fonction AF-2 du ERα. Ces résultats ouvrent la voie à une modulation sélective du récepteur activant spécifiquement AF-2 dans une perspective de prévention cardiovasculaire et métabolique.
    Diabetes & Metabolism 09/2012; 73(4):261–262. DOI:10.1016/j.ando.2012.07.091 · 2.85 Impact Factor
  • 39th Annual Congress of the European-Calcified-Tissue-Society (ECTS); 05/2012
  • 39th Annual Congress of the European-Calcified-Tissue-Society (ECTS); 05/2012
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    ABSTRACT: High estradiol levels in late puberty induce growth plate closure and thereby cessation of growth in humans. In mice, the growth plates do not fuse after sexual maturation, but old mice display reduced longitudinal bone growth and high-dose estradiol treatment induces growth plate closure. Estrogen receptor (ER)-α stimulates gene transcription via two activation functions (AFs), AF-1 and AF-2. To evaluate the role of ERα and its AF-1 for age-dependent reduction in longitudinal bone growth and growth plate closure, female mice with inactivation of ERα (ERα(-/-)) or ERαAF-1 (ERαAF-1(0)) were evaluated. Old (16- to 19-mo-old) female ERα(-/-) mice showed continued substantial longitudinal bone growth, resulting in longer bones (tibia: +8.3%, P < 0.01) associated with increased growth plate height (+18%, P < 0.05) compared with wild-type (WT) mice. In contrast, the longitudinal bone growth ceased in old ERαAF-1(0) mice (tibia: -4.9%, P < 0.01). Importantly, the proximal tibial growth plates were closed in all old ERαAF-1(0) mice while they were open in all WT mice. Growth plate closure was associated with a significantly altered balance between chondrocyte proliferation and apoptosis in the growth plate. In conclusion, old female ERα(-/-) mice display a prolonged and enhanced longitudinal bone growth associated with increased growth plate height, resembling the growth phenotype of patients with inactivating mutations in ERα or aromatase. In contrast, ERαAF-1 deletion results in a hyperactive ERα, altering the chondrocyte proliferation/apoptosis balance, leading to growth plate closure. This suggests that growth plate closure is induced by functions of ERα that do not require AF-1 and that ERαAF-1 opposes growth plate closure.
    AJP Endocrinology and Metabolism 03/2012; 302(11):E1381-9. DOI:10.1152/ajpendo.00646.2011 · 4.09 Impact Factor
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    ABSTRACT: Rationnel Les œstrogènes préviennent l’accumulation de masse grasse et la survenue d’un diabète de type 2 via leur récepteur α(ERα), mais leurs effets indésirables limitent leur intérêt thérapeutique. ER_régule la transcription de nombreux gènes grâce à ses deux fonctions de transactivation, AF-1 et AF-2, et nous avons montré que, en activant le récepteur indépendamment de la fonction AF-1, il est possible de conserver l’intégralité des actions vasculoprotectrices des oestrogènes sans effet délétère sur l’utérus. Matériels et méthodes Pour étudier l’implication des fonctions de transactivation de ER_dans l’action bénéfique des oestrogènes sur la composition corporelle et l’homéostasie glucidique, des souris déficientes en ERα(ERα-/-), en AF-1 (AF-1-/-) ou AF-2 (AF-2-/-), ont été suivies jusqu’à l’âge de 7 mois (régime standard, mâles et femelles, n = 8–10 par sexe et par génotype). Résultats Par comparaison à leurs contrôles sauvages, les souris ERα-/- ont été caractérisées par une prise de poids accélérée avec accumulation massive de tissu adipeux, une insulinorésistance et une intolérance au glucose. Les souris AF-2-/- ont développé un profil phénotypique et métabolique identique. En revanche, nous n’avons pas observé d’accélération du gain pondéral et du développement de la masse grasse chez les animaux AF-1-/-. De plus, la tolérance au glucose était conservée chez les mâles, et altérée uniquement tardivement chez les femelles AF-1-/-. De façon concordante, l’effet protecteur de l’administration chronique de 17β-estradiol vis-à-vis de l’accumulation de tissu adipeux chez des femelles ovariectomisées était aboli chez les souris ERα-/- et AF-2-/-, mais totalement conservé chez les souris AF-1-/-. Conclusion Comme pour leurs effets vasculoprotecteurs, l’action favorable des oestrogènes sur la masse grasse et la tolérance au glucose est en grande partie indépendante de la fonction AF-1 du ERα. Ces résultats ouvrent la voie à une modulation sélective du récepteur n’activant pas AF-1 dans une perspective de prévention cardiovasculaire et métabolique.
    Diabetes & Metabolism 03/2011; 37(1):A2. DOI:10.1016/S1262-3636(11)70495-5 · 2.85 Impact Factor
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    ABSTRACT: The bone-sparing effect of estrogen is primarily mediated via estrogen receptor-α (ERα), which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand binding domain. To evaluate the role of ERα AF-1 and ERα AF-2 for the effects of estrogen in bone in vivo, we analyzed mouse models lacking the entire ERα protein (ERα(-/-)), ERα AF-1 (ERαAF-1(0)), or ERα AF-2 (ERαAF-2(0)). Estradiol (E2) treatment increased the amount of both trabecular and cortical bone in ovariectomized (OVX) WT mice. Neither the trabecular nor the cortical bone responded to E2 treatment in OVX ERα(-/-) or OVX ERαAF-2(0) mice. OVX ERαAF-1(0) mice displayed a normal E2 response in cortical bone but no E2 response in trabecular bone. Although E2 treatment increased the uterine and liver weights and reduced the thymus weight in OVX WT mice, no effect was seen on these parameters in OVX ERα(-/-) or OVX ERαAF-2(0) mice. The effect of E2 in OVX ERαAF-1(0) mice was tissue-dependent, with no or weak E2 response on thymus and uterine weights but a normal response on liver weight. In conclusion, ERα AF-2 is required for the estrogenic effects on all parameters evaluated, whereas the role of ERα AF-1 is tissue-specific, with a crucial role in trabecular bone and uterus but not cortical bone. Selective ER modulators stimulating ERα with minimal activation of ERα AF-1 could retain beneficial actions in cortical bone, constituting 80% of the skeleton, while minimizing effects on reproductive organs.
    Proceedings of the National Academy of Sciences 03/2011; 108(15):6288-93. DOI:10.1073/pnas.1100454108 · 9.81 Impact Factor
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    ABSTRACT: Post-menopausal women have an increased risk of developing a number of degenerative pathological conditions, linked by the common theme of excessive inflammation. Systemic estrogen replacement (in the form of hormone replacement therapy) is able to accelerate healing of acute cutaneous wounds in elderly females, linked to its potent antiinflammatory activity. However, in contrast to many other age-associated pathologies, the detailed mechanisms through which estrogen modulates skin repair, particularly the cell type-specific role of the two estrogen receptors, ERalpha and ERbeta, has yet to be determined. Here, we use pharmacological activation and genetic deletion to investigate the role of both ERalpha and ERbeta in cutaneous tissue repair. Unexpectedly, we report that exogenous estrogen replacement to ovariectomised mice in the absence of ERbeta actually delayed wound healing. Moreover, healing in epidermal-specific ERbeta null mice (K14-cre/ERbeta(L2/L2)) largely resembled that in global ERbeta null mice. Thus, the beneficial effects of estrogen on skin wound healing are mediated by epidermal ERbeta, in marked contrast to most other tissues in the body where ERalpha is predominant. Surprisingly, agonists to both ERalpha and ERbeta are potently antiinflammatory during skin repair, indicating clear uncoupling of inflammation and overall efficiency of repair. Thus, estrogen-mediated antiinflammatory activity is not the principal factor in accelerated wound healing.
    Journal of Experimental Medicine 08/2010; 207(9):1825-33. DOI:10.1084/jem.20100500 · 13.91 Impact Factor
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    ABSTRACT: Full-length 66-kDa estrogen receptorα (ERα) stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal domain and AF-2 in the ligand binding domain. Another physiologically expressed 46-kDa ERα isoform lacks the N-terminal A/B domains and is consequently devoid of AF-1. Previous studies in cultured endothelial cells showed that the N-terminal A/B domain might not be required for estradiol (E2)-elicited NO production. To evaluate the involvement of ERαAF-1 in the vasculoprotective actions of E2, we generated a targeted deletion of the ERα A/B domain in the mouse. In these ERαAF-1zero mice, both basal endothelial NO production and reendothelialization process were increased by E2 administration to a similar extent than in control mice. Furthermore, exogenous E2 similarly decreased fatty streak deposits at the aortic root from both ovariectomized 18-weekold ERαAF-1+/+LDLR-/- (low-density lipoprotein receptor) and ERαAF-1zeroLDLR-/- mice fed with a hypercholesterolemic diet. In addition, quantification of lesion size on en face preparations of the ic tree of 8-month-old ovariectomized or intact female mice revealed that ERαAF-1 is dispensable for the atheroprotective action of endogenous estrogens. We conclude that ERαAF-1 is not required for three major vasculoprotective actions of E2, whereas it is necessary for the effects of E2 on its reproductive targets. Thus, selective ER modulators stimulating ERα with minimal activation of ERαAF-1 could retain beneficial vascular actions, while minimizing the sexual effects.
    Archives of Cardiovascular Diseases 03/2009; 102. DOI:10.1016/S1875-2136(09)72140-0 · 1.66 Impact Factor
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    ABSTRACT: Estrogen represents an important factor for the development and function of the nigrostriatal dopamine system. Estrogen also controls sex-specific differentiation and activity of the nigrostriatal dopaminergic system. We used an estrogen receptor-alpha knockout (-/-) model (ERKO) to study the influence of this particular receptor subtype on the regulation of functional characteristics of the male and female nigrostriatal dopamine system. On the striatal level, we found a sex-specific regulation of dopamine D1 receptors (D1) and dopamine receptor-interacting protein 78 (Drip78). In female (-/-) mice D1 receptor expression levels were increased compared to wild type (wt) animals, whereas in male (-/-) mice Drip78 mRNA levels were decreased compared to wt. In the midbrain, expression of tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF) was reduced in (-/-) mice of both sexes. Glial cell line-derived neurotrophic factor (GDNF) expression was not affected. These data demonstrate that the integrity of estrogen receptor-alpha (ERalpha) signalling is necessary for the regulation of gene expression of proteins known to be important for the function of the nigrostriatal system at the postsynaptic striatal and presynaptic midbrain level.
    Psychoneuroendocrinology 08/2008; 33(6):832-8. DOI:10.1016/j.psyneuen.2008.03.007 · 5.59 Impact Factor
  • Annals of the New York Academy of Sciences 12/2006; 464(1):443 - 447. DOI:10.1111/j.1749-6632.1986.tb16031.x · 4.31 Impact Factor
  • Annals of the New York Academy of Sciences 12/2006; 469(1):18 - 30. DOI:10.1111/j.1749-6632.1986.tb26481.x · 4.31 Impact Factor
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    ABSTRACT: Recent studies have revealed that hundreds of genes in the uterus are activated by estrogen. Their expression profiles differ over time and doses and it is not clear whether all these genes are directly regulated by estrogen via the estrogen receptor. To select the genes that may be regulated by estrogen, we treated mice with several doses of estrogen and searched for those genes whose dose-response expression pattern mirrored the uterine growth pattern. Among those genes, we found that the dose-dependent expression of the adrenomedullin (ADM) gene correlated well with the uterotrophic effect of estrogen. ADM expression is induced early after estrogen administration and is restricted to the endometrial stroma. The spatiotemporal gene expression pattern of ADM was similar to that of receptor-modifying protein 3 (RAMP3). RAMP3 is known to modify calcitonin gene-related receptor (CRLR) so that it can then serve as an ADM receptor. Chromatin immunoprecipitation assays indicated that the estrogen receptor binds directly to the ADM promoter region and RAMP3 intron after estrogen administration. It was also shown that neither the ADM nor RAMP3 gene could be activated in estrogen receptor-alpha-null mouse. Although uterine ADM expression has been reported to occur in the myometrium, our observations indicate that estrogen-induced ADM is also expressed in the uterine stroma and that such variable, spatiotemporally regulated ADM expression contributes to a wider range of biological effects than previously expected.
    Journal of Molecular Endocrinology 03/2006; 36(1):81-9. DOI:10.1677/jme.1.01825 · 3.62 Impact Factor
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    ABSTRACT: Estrogens influence CNS development and a broad spectrum of neural functions. Several lines of evidence also suggest a neuroprotective role for estrogen. Different modes of estrogen action have been described at the cellular level involving classical nuclear estrogen receptor (ER)-dependent and nonclassical membrane ER-mediated rapid signaling. We have previously shown that nonclassical estrogen signaling is implicated in the control of dopamine cell function and protection. Since nonclassical interactions between estrogens and glia may contribute to these effects, our aim was to demonstrate the presence of membrane-associated ERs and their putative coupling to intracellular signaling pathways in astrocytes. Confocal image analysis and fluorescence-activated cell sorting (FACS) studies indicated the attachment of ER-alpha but not ER-beta to the plasma membrane of astrocytes. ERs were located in the cell soma region and glial processes. FACS analysis revealed that only a subpopulation of midbrain astrocytes possesses membrane ER-alpha. In FACS studies on ER-alpha knockout astrocytes, only a few membrane ER-positive cells were detected. The activation of membrane ERs appears to be coupled to the MAP-kinase/Src signaling pathway as shown by Western blotting. In conclusion, our data provide good evidence that nonclassical estrogen action in astrocytes is mediated by membrane ER-alpha. The physiological consequence of this phenomenon is not yet understood, but it might have a pivotal role in estrogen-mediated protective effects on midbrain dopamine neurons.
    Glia 05/2005; 50(3):270-5. DOI:10.1002/glia.20162 · 6.03 Impact Factor
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    ABSTRACT: Estrogen regulates proliferation and differentiation of epithelial cells in the mammalian oviduct, but pathways for cell-specific differentiation are not well understood. In the epithelial cells of the developing rat oviduct, we found estrogen receptor (ER) alpha is expressed at birth and persists in all cells through neonatal day (ND) 7 when ciliated cells appear. To determine a specific function of ER and foxj1, a transcription factor known to have fundamental roles in ciliogenesis in the lung, in differentiation of the ciliated epithelial cells, we treated newborn rats from ND 0 to 5 with estradiol-17beta (E2) with and without a selective ER antagonist. E2 enhanced the number of proliferating cells and accelerated the process of epithelial cell differentiation resulting in ciliogenesis by ND 5, and co-treatment with an ER antagonist inhibited these changes. Foxj1 was expressed only in the infundibulum and ampulla (INF/AMP). That expression preceded the appearance of cilia and was induced by E2. Cilia were absent in oviducts of foxj1-deficient mice, indicating that foxj1 plays a critical role in oviductal ciliogenesis. However, we found the presence of cilia in the ERalpha-deficient mouse oviduct. The widespread expression of ERalpha in oviductal epithelium, but restriction of cilia to the INF/AMP regions, and importantly, the presence of cilia in the ERalpha-deficient mice, suggested ER signaling is not essential for ciliated epithelial cell differentiation. These observations demonstrate that, although E2 stimulates the differentiation process of ciliated epithelial cells, foxj1 is directly required for epithelial cell ciliogenesis of the neonatal oviduct.
    Journal of Molecular Endocrinology 07/2004; 32(3):615-25. · 3.62 Impact Factor
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    ABSTRACT: Both 17beta-estradiol (E2) and fibroblast growth factor-2 (FGF2) stimulate angiogenesis and endothelial cell migration and proliferation. The first goal of this study was to explore the potential link between this hormone and this growth factor. E2-stimulated angiogenesis in SC Matrigel plugs in Fgf2+/+ mice, but not in Fgf2-/- mice. Cell cultures from subcutaneous Matrigel plugs demonstrated that E2 increased both migration and proliferation in endothelial cells from Fgf2+/+ mice, but not from in Fgf2-/- mice. Several isoforms of fibroblast growth factor-2 (FGF2) are expressed: the low molecular weight 18-kDa protein (FGF2lmw) is secreted and activates tyrosine kinase receptors (FGFRs), whereas the high molecular weight (21 and 22 kDa) isoforms (FGF2hmw) remains intranuclear, but their role is mainly unknown. The second goal of this study was to explore the respective roles of FGF2 isoforms in the effects of E2. We thus generated mice deficient only in the FGF2lmw (Fgf2lmw-/-). E2 stimulated in vivo angiogenesis and in vitro migration in endothelial cells from Fgf2lmw-/- as it did in Fgf2+/+ mice. E2 increased FGF2hmw protein abundance in endothelial cell cultures from Fgf2+/+ and Fgf2lmw-/- mice. As shown using siRNA transfection, these effects were FGFR independent but involved FGF2-Interacting Factor, an intracellular FGF2hmw partner. This is the first report for a physiological role for the intracellular FGF2hmw found to mediate the effect of E2 on endothelial cell migration via an intracrine action.
    Circulation Research 06/2004; 94(10):1301-9. DOI:10.1161/01.RES.0000127719.13255.81 · 11.09 Impact Factor
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    ABSTRACT: Although estradiol (E(2)) has been recognized to exert several vasculoprotective effects in several species, its effects in mouse vasomotion are unknown, and consequently, so is the estrogen receptor subtype mediating these effects. We investigated the effect of E(2) (80 microg/kg/day for 15 days) on NO production in the thoracic aorta of ovariectomized C57Bl/6 mice compared with those given placebo. E(2) increased basal NO production. In contrast, the relaxation in response to ATP, to the calcium ionophore A23187, and to sodium nitroprusside was unaltered by E(2), whereas acetylcholine-elicited relaxation was decreased. The abundance of NO synthase I, II, and III immunoreactive proteins (using Western blot) in thoracic aorta homogenates was unchanged by E(2). To determine the estrogen receptor (ER) subtype involved in these effects, transgenic mice in which either the ERalpha or ERbeta has been disrupted were ovariectomized and treated, or not, with E(2). Basal NO production was increased and the sensitivity to acetylcholine decreased in ERbeta knockout mice in response to E(2), whereas this effect was abolished in ERalpha knockout mice. Finally, these effects of E(2) on vasomotion required long-term and/or in vivo exposure, as short-term incubation of aortic rings with 10 nmol/L E(2) in the isolated organ chamber did not elicit any vasoactive effects. In conclusion, this study demonstrates that ERalpha, but not ERbeta, mediates the beneficial effect of E(2) on basal NO production.
    Circulation Research 04/2002; 90(4):413-9. · 11.09 Impact Factor
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    ABSTRACT: Two isoforms of estrogen receptor (ER) have been described: ERalpha and ERbeta. The initial gene targeting of ERalpha, consisting in the introduction of a Neo cassette in exon 1 [alphaERKO, hereafter called ERalpha-Neo KO (knockout)], was reported in 1993. More recently, another mouse deficient in ERalpha because of the deletion of exon 2 (ERalphaKO, hereafter called ERalpha-delta2 KO) was generated. In ovariectomized ERalpha-wild-type mice, estradiol (E(2)) increases uterine weight and basal production of endothelial nitric oxide (NO). Both of these effects are abolished in ERalpha-delta2 KO mice. In contrast, we show here that both of these effects of E(2) are partially (uterine weight) or totally (endothelial NO production) preserved in ERalpha-Neo KO. We also confirm the presence of two ERalpha mRNA splice variants in uterus and aorta from ERalpha-Neo KO mice. One of them encodes a chimeric ERalpha protein (ERalpha55), partially deleted in the A/B domain, that was detected in both uterus and aorta by Western blot analysis. The other ERalpha mRNA splice variant codes for an isoform deleted for the A/B domain (ERalpha46), which was detected in uterus of ERalpha-Neo KO, and wild-type mice. This protein isoform was not detected in aorta. The identification of these two N-terminal modified isoforms in uterus, and at least one of them in aorta, probably explains the persistence of the E(2) effects in ERalpha-Neo KO mice. Furthermore, ERalpha-Neo KO mice may help in the elucidation of the specific functions of full-length ERalpha (ERalpha66) and ERalpha46, both shown to be physiologically generated in vivo.
    Proceedings of the National Academy of Sciences 03/2002; 99(4):2205-10. DOI:10.1073/pnas.042688499 · 9.81 Impact Factor

Publication Stats

7k Citations
408.71 Total Impact Points

Institutions

  • 2000–2012
    • Collège de France
      Lutetia Parisorum, Île-de-France, France
  • 2002–2011
    • Institut de Génétique et de Biologie Moléculaire et Cellulaire
      Strasburg, Alsace, France
    • Institut Louis Bachelier
      Lutetia Parisorum, Île-de-France, France
  • 1990–2011
    • French Institute of Health and Medical Research
      • Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) U964
      Paris, Ile-de-France, France
  • 2004
    • University of Cincinnati
      Cincinnati, Ohio, United States
  • 1986–1989
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
    • University of Chicago
      Chicago, Illinois, United States