Gestational exposure to ethanol suppresses msx2 expression in developing mouse embryos

Rifas, Leonard; Towler, Dwight A.; Avioli, Louis V.

doi:10.1073/pnas.94.14.7549

Cited by 41 publications

(25 citation statements)

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“…Whether Msx2 participates in the regulation of multiple FGF-activated gene targets is currently unknown; however, Msx2 does not inhibit FGF2 induction of the interstitial collagenase promoter, 3 a signaling pathway pharmacologically distinct from the cascade activating the OCFRE (33). Intriguingly, in utero exposure to alcohol down-regulates Msx2 expression in the developing embryo (34). It will be interesting to assess whether fetal alcohol exposure dysregulates temporospatial responses to FGF during tissue morphogenesis.…”

Section: Discussionmentioning

confidence: 99%

Stimulus-selective Inhibition of Rat Osteocalcin Promoter Induction and Protein-DNA Interactions by the Homeodomain Repressor Msx2

Newberry

Boudreaux

Towler

1997

Journal of Biological Chemistry

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Osteocalcin (OC) is a matrix calcium-binding protein expressed in osteoblasts and odontoblasts undergoing mineralization. OC expression is up-regulated in part by signals initiated by basic fibroblast growth factor (FGF2), cyclic AMP or forskolin (FSK), and calcitriol via defined elements and DNA-protein interactions in the OC promoter. We identified the OC gene as a target for transcriptional suppression by Msx2, a homeodomain transcription factor that controls ossification in the developing skull. In this study, we examine the effects of Msx2 expression on OC promoter activation (luciferase reporter) by FGF2/FSK and calcitriol in MC3T3-E1 osteoblasts. Expression of Msx2 decreases basal activity of the 1-kilobase (؊1050 to ؉32) rat OC promoter by 80%; however, the promoter is still inducible 3-fold by calcitriol. By contrast, OC promoter induction by FGF2/FSK is completely abrogated by Msx2. Because intrinsic Msx2 DNA binding activity is not required for the Msx2 suppressor function, we assessed whether Msx2 represses OC activation by regulating DNA-protein interactions at the FGF2 response element (OCFRE) and compared these interactions with those occurring at the calcitriol response element (VDRE). Treatment of MC3T3-E1 cells with FGF2/FSK or calcitriol up-regulates specific DNAprotein interactions at the OCFRE or VDRE, respectively, as detected by gel shift assay. Preincubation of crude nuclear extracts with recombinant glutathione S-transferase (GST)-Msx2 dose-dependently inhibits OCFRE DNA binding activity, whereas GST has no effect. Msx2 itself does not bind the OCFRE. Residues 132-148 required for Msx2 core suppressor function in transfection assays are also required to inhibit OCFRE DNA binding activity. By contrast, GST-Msx2 has no effect on calcitriol-regulated DNA-protein interactions at the VDRE. Using gel shift as an assay, the OCFRE DNA-binding protein OCFREB was purified to about 50% homogeneity from MG63 osteosarcoma cells. Recombinant Msx2 inhibits purified OCFREB DNA binding activity, whereas the Msx2 variant lacking residues 132-148 is inactive. Thus, Msx2 abrogates up-regulation of the OC promoter by FGF2/FSK in part by inhibiting OCFREB binding to the OCFRE.

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Section: Discussionmentioning

confidence: 99%

Stimulus-selective Inhibition of Rat Osteocalcin Promoter Induction and Protein-DNA Interactions by the Homeodomain Repressor Msx2

Newberry

Boudreaux

Towler

1997

Journal of Biological Chemistry

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“…Cardiac malformations exist in children with fetal alcohol syndrome (44,53) and animal models of prenatal alcohol exposure (43,57), and cardiac hypertrophy has been found in children with fetal alcohol syndrome (68). Prenatal ethanol exposure has been shown to cause ultrastructural abnormalities in cardiac muscle cells in mice (63) and a significant difference in left ventricular muscle width in male rats (41).…”

Section: Discussionmentioning

confidence: 99%

Sexually dimorphic effects of maternal alcohol intake and adrenalectomy on left ventricular hypertrophy in rat offspring

Wilcoxon

Schwartz

Aird³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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In humans, low birth weight and increased placental weight can be associated with cardiovascular disease in adulthood. Low birth weight and increased placental size are known to occur after fetal alcohol exposure or prenatal glucocorticoid administration. Thus the effects of removing the alcohol-induced increase in maternal corticosterone by maternal adrenalectomy on predictors of cardiovascular disease in adulthood were examined in rats. Alcohol exposure of dams during the last 2 wk of gestation resulted in significantly decreased fetal weight and increased placental weight on gestational day 21. Adult female, but not male, offspring of alcohol-consuming mothers exhibited left ventricular hypertrophy. Placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD-2) mRNA levels, measured by Northern blot, were decreased in females but not males. Adrenalectomy of alcohol-consuming dams reversed the increase in placental weight and the decrease in female placental 11β-HSD-2 expression and eliminated the left ventricular hypertrophy of adult female offspring. These data suggest that alcohol-induced changes in placental 11β-HSD-2 mRNA levels and left ventricular weight are coupled in female offspring only and depend on maternal adrenal status.

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“…Statistics-Statistical analyses were performed using Student's unpaired t test or one-way analysis of variance as previously detailed (22). Each experiment was performed at least twice, and the representative data were presented as mean Ϯ S.E.…”

Section: Methodsmentioning

confidence: 99%

Msx2 Promotes Osteogenesis and Suppresses Adipogenic Differentiation of Multipotent Mesenchymal Progenitors

Cheng

Shao

Charlton-Kachigian

et al. 2003

Journal of Biological Chemistry

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321

300

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In the aorta, diabetes activates an osteogenic program that includes expression of bone morphogenetic protein-2 (BMP2) and the osteoblast homeoprotein Msx2. To evaluate BMP2-Msx2 signaling in vascular calcification, we studied primary aortic myofibroblasts. These cells express vascular smooth muscle cell (VSMC) markers, respond to BMP2 by up-regulating Msx2, and undergo osteogenic differentiation with BMP2 treatment or transduction with a virus encoding Msx2. The osteoblast factor osterix (Osx) is up-regulated 10-fold by Msx2, but Runx2 mRNA is unchanged; the early osteoblast marker alkaline phosphatase increases 50-fold with mineralized nodule formation enhanced 30-fold. Adipocyte markers are concomitantly suppressed. To better understand Msx2 actions on osteogenesis versus adipogenesis, mechanistic studies were extended to C3H10T1/2 mesenchymal cells. Msx2 enhances osteogenic differentiation in synergy with BMP2. Osteogenic actions depend upon intrinsic Msx2 DNA binding; the gain-of-function variant Msx2(P148H) directs enhanced mineralization, whereas the binding-deficient variant Msx2(T147A) is inactive. Adipogenesis (lipid accumulation, Pparg expression) is inhibited by Msx2. By contrast, suppression of adipogenesis does not require Msx2 DNA binding; inhibition occurs in part via proteinprotein interactions with C/EBP␣ that control Pparg transcription. Thus, Msx2 regulates osteogenic versus adipogenic differentiation of aortic myofibroblasts. Myofibroblasts capable of both fates can be diverted to the osteogenic lineage by BMP2-Msx2 signaling and contribute to vascular calcification.Mineral deposition in the skeleton is regulated by morphogenetic, metabolic, mechanical, inflammatory, and endocrine factors. With aging, abnormalities in orthotopic (e.g. bone formation) and heterotopic arterial vascular calcification are observed with very high prevalence (1), the latter enhanced by hyperglycemia, hyperlipidemia, and chronic renal insufficiency (1, 2). At least three variants of vascular calcification have been described: (a) calcification of necrotic, intimal atherosclerotic plaques; (b) medial artery calcification; and (c) calcific sclerosis of the aortic valve. Vascular calcification is a highly significant complication of diabetes and has emerged as a powerful predictor of cardiovascular morbidity and mortality (2). The molecular mechanisms that perturb normal vascular calcium metabolism are only beginning to be understood (1, 3, 4). Demer et al. (5) was the first to show that vascular calcification may progress via molecular processes similar to osteogenesis. This group showed that the powerful bone morphogen, bone morphogenetic protein 2 (BMP2) 1 is expressed in calcified atherosclerotic plaques of humans (5). Bostrom et al. (6) further demonstrated that aortic calcification in response to matrix Gla protein deficiency was most likely via BMP2 signaling; matrix Gla protein can abrogate alkaline phosphatase (ALP) induction by inhibiting BMP2 association with the BMP receptor (6). Thus, these studies poi...

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Gestational exposure to ethanol suppresses msx2 expression in developing mouse embryos

Cited by 41 publications

References 74 publications

Stimulus-selective Inhibition of Rat Osteocalcin Promoter Induction and Protein-DNA Interactions by the Homeodomain Repressor Msx2

Stimulus-selective Inhibition of Rat Osteocalcin Promoter Induction and Protein-DNA Interactions by the Homeodomain Repressor Msx2

Sexually dimorphic effects of maternal alcohol intake and adrenalectomy on left ventricular hypertrophy in rat offspring

Msx2 Promotes Osteogenesis and Suppresses Adipogenic Differentiation of Multipotent Mesenchymal Progenitors

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