4 research outputs found
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Effects of 12 months of voluntary alcohol self-administration on intracortical bone remodeling in a rhesus macaque model
Background: Alcohol is a nonessential nutrient widely consumed throughout the world. Chronic alcohol abuse is associated with numerous adverse skeletal effects. However, prior to this study, the effects of alcohol abuse on intracortical bone remodeling in an animal model had not been investigated. Reduced intracortical bone remodeling could impair repair of microdamage accrued during activities of daily living and lead to increased risk of bone fractures. Methods: To fill this gap in knowledge, we investigated the effects of 12 months of voluntary self-administration of ethanol (4% v/v) on bone mass, bone microarchitecture, and intracortical bone remodeling in male rhesus monkeys approaching skeletal maturity (mean age 6.7 years). Results: Alcohol-fed monkeys consumed a mean of 2.8 g/kg ethanol per day. No significant difference was found between alcohol and control monkeys for body weight, age, or any indices of bone mass or bone microarchitecture. However, monkeys in the alcohol group had significantly lower intracortical bone formation and bone resorption compared to the control group. Conclusions: These results suggest that 12-months of self-administration of alcohol results in significantly reduced intracortical bone remodeling without affecting bone mass or bone microarchitecture; thus, evidence from this study indicates that alcohol abuse can reduce bone quality without affecting bone quantity
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Twelve months of voluntary heavy alcohol consumption in male rhesus macaques suppresses intracortical bone remodeling
Chronic heavy alcohol consumption is a risk factor for cortical bone fractures in males. The increase in fracture
risk may be due, in part, to reduced bone quality. Intracortical (osteonal) bone remodeling is the principle
mechanism for maintaining cortical bone quality. However, it is not clear how alcohol abuse impacts intracortical
bone remodeling. This study investigated the effects of long-duration heavy alcohol consumption on intracortical
bone remodeling in a non-human primate model. Following a 4-month induction period, male rhesus macaques
(Macaca mulatta, n = 21) were allowed to voluntarily self-administer water or alcohol (4% ethanol w/v) for
22 h/d, 7 d/wk for 12 months. Control monkeys (n = 13) received water and an isocaloric maltose-dextrin solution.
Tetracycline hydrochloride was administered orally 17 and 3 days prior to sacrifice for determination of
active mineralization sites. Animals in the alcohol group consumed 2.7 Ā± 0.2 g alcohol/kg/d (mean Ā± SE) during
the 12 months of self-administration, resulting in a mean daily blood alcohol concentration of 77 Ā± 9 mg/dl from
samples taken at 7 h after the start of a daily session. However, blood alcohol concentration varied widely
from day to day, with peak levels exceeding 250 mg/dl, modeling a binge-drinking pattern of alcohol consumption.
The skeletal response to alcohol was determined by densitometry, microcomputed tomography and
histomorphometry. Significant differences in tibial bone mineral content, bone mineral density, and cortical
bone architecture (cross-sectional volume, cortical volume, marrow volume, cortical thickness, and polar
moment of inertia) in the tibial diaphysis were not detected with treatment. However, cortical porosity was
lower (1.8 Ā± 0.5 % versus 0.6 Ā± 0.1 %, p = 0.021) and labeled osteon density was lower (0.41 Ā± 0.2/mmĀ² versus
0.04 Ā± 0.01/mmĀ², p < 0.003) in alcohol-consuming monkeys compared to controls, indicating a reduced rate of
intracortical bone remodeling. In concordance, plasma CTx was lower (2.5 Ā± 0.3 ng/ml versus 1.7 Ā± 0.1 ng/ml,
p = 0.028) in the alcohol group. These results suggest that chronic heavy alcohol consumption may negatively
impact bone health, in part, by suppressing intracortical bone remodeling.Keywords: Ethanol, Histomorphometry, Non-human primate, Haversian remodeling, Microcomputed tomograph
Identification of Genetic Modifiers of CagA-Induced Epithelial Disruption in Drosophila
Helicobacter pylori strains containing the CagA protein are associated with high risk of gastric diseases including atrophic gastritis, peptic ulcers, and gastric cancer. CagA is injected into host cells via a Type IV secretion system where it activates growth factor-like signaling, disrupts cell-cell junctions, and perturbs host cell polarity. Using a transgenic Drosophila model, we have shown that CagA expression disrupts the morphogenesis of epithelial tissues such as the adult eye. Here we describe a genetic screen to identify modifiers of CagA-induced eye defects. We determined that reducing the copy number of genes encoding components of signaling pathways known to be targeted by CagA, such as the epidermal growth factor receptor, modified the CagA-induced eye phenotypes. In our screen of just over half the Drosophila genome, we discovered 12 genes that either suppressed or enhanced CagAās disruption of the eye epithelium. Included in this list are genes involved in epithelial integrity, intracellular trafficking, and signal transduction. We investigated the mechanism of one suppressor, encoding the epithelial polarity determinant and junction protein Coracle, which is homologous to the mammalian Protein 4.1. We found that loss of a single copy of coracle improved the organization and integrity of larval retinal epithelia expressing CagA, but did not alter CagAās localization to cell junctions. Loss of a single copy of the coracle antagonist crumbs enhanced CagA-associated disruption of the larval retinal epithelium, whereas overexpression of crumbs suppressed this phenotype. Collectively, these results point to new cellular pathways whose disruption by CagA are likely to contribute to H. pylori-associated disease pathology