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Research ArticleToxicology

Chronic Ethanol Feeding in Mice Decreases Expression of Genes for Major Structural Bone Proteins in a Nox4-Independent Manner

Kim B. Pedersen, Michelle L. Osborn, Alex C. Robertson, Ashlee E. Williams, James Watt, Alexandra Denys, Katrin Schröder and Martin J. Ronis
Journal of Pharmacology and Experimental Therapeutics June 2020, 373 (3) 337-346; DOI: https://doi.org/10.1124/jpet.119.264374
Kim B. Pedersen
Department of Pharmacology & Experimental Therapeutics, Louisiana State Health Sciences Center (LSUHSC), New Orleans, Louisiana (K.B.P., A.C.R., A.E.W., J.W., A.D., M.J.R.); Comparative Biomedical Sciences, Louisiana State University (LSU) School of Veterinary Medicine, Baton Rouge, Louisiana (M.L.O.); and Institute of Physiology I, Goethe-University, Frankfurt, Germany (K.S.)
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Michelle L. Osborn
Department of Pharmacology & Experimental Therapeutics, Louisiana State Health Sciences Center (LSUHSC), New Orleans, Louisiana (K.B.P., A.C.R., A.E.W., J.W., A.D., M.J.R.); Comparative Biomedical Sciences, Louisiana State University (LSU) School of Veterinary Medicine, Baton Rouge, Louisiana (M.L.O.); and Institute of Physiology I, Goethe-University, Frankfurt, Germany (K.S.)
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Alex C. Robertson
Department of Pharmacology & Experimental Therapeutics, Louisiana State Health Sciences Center (LSUHSC), New Orleans, Louisiana (K.B.P., A.C.R., A.E.W., J.W., A.D., M.J.R.); Comparative Biomedical Sciences, Louisiana State University (LSU) School of Veterinary Medicine, Baton Rouge, Louisiana (M.L.O.); and Institute of Physiology I, Goethe-University, Frankfurt, Germany (K.S.)
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Ashlee E. Williams
Department of Pharmacology & Experimental Therapeutics, Louisiana State Health Sciences Center (LSUHSC), New Orleans, Louisiana (K.B.P., A.C.R., A.E.W., J.W., A.D., M.J.R.); Comparative Biomedical Sciences, Louisiana State University (LSU) School of Veterinary Medicine, Baton Rouge, Louisiana (M.L.O.); and Institute of Physiology I, Goethe-University, Frankfurt, Germany (K.S.)
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James Watt
Department of Pharmacology & Experimental Therapeutics, Louisiana State Health Sciences Center (LSUHSC), New Orleans, Louisiana (K.B.P., A.C.R., A.E.W., J.W., A.D., M.J.R.); Comparative Biomedical Sciences, Louisiana State University (LSU) School of Veterinary Medicine, Baton Rouge, Louisiana (M.L.O.); and Institute of Physiology I, Goethe-University, Frankfurt, Germany (K.S.)
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Alexandra Denys
Department of Pharmacology & Experimental Therapeutics, Louisiana State Health Sciences Center (LSUHSC), New Orleans, Louisiana (K.B.P., A.C.R., A.E.W., J.W., A.D., M.J.R.); Comparative Biomedical Sciences, Louisiana State University (LSU) School of Veterinary Medicine, Baton Rouge, Louisiana (M.L.O.); and Institute of Physiology I, Goethe-University, Frankfurt, Germany (K.S.)
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Katrin Schröder
Department of Pharmacology & Experimental Therapeutics, Louisiana State Health Sciences Center (LSUHSC), New Orleans, Louisiana (K.B.P., A.C.R., A.E.W., J.W., A.D., M.J.R.); Comparative Biomedical Sciences, Louisiana State University (LSU) School of Veterinary Medicine, Baton Rouge, Louisiana (M.L.O.); and Institute of Physiology I, Goethe-University, Frankfurt, Germany (K.S.)
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Martin J. Ronis
Department of Pharmacology & Experimental Therapeutics, Louisiana State Health Sciences Center (LSUHSC), New Orleans, Louisiana (K.B.P., A.C.R., A.E.W., J.W., A.D., M.J.R.); Comparative Biomedical Sciences, Louisiana State University (LSU) School of Veterinary Medicine, Baton Rouge, Louisiana (M.L.O.); and Institute of Physiology I, Goethe-University, Frankfurt, Germany (K.S.)
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Abstract

Bone loss in response to alcohol intake has previously been hypothesized to be mediated by excessive production of reactive oxygen species via NADPH oxidase (Nox) enzymes. Nox4 is one of several Nox enzymes expressed in bone. We investigated the role of Nox4 in the chondro-osteoblastic lineage of the long bones in mice during normal chow feeding and during chronic ethanol feeding for 90 days. We generated mice with a genotype (PrxCre +/− Nox4 fl/fl) allowing conditional knockout of Nox4 in the limb bud mesenchyme. Adult mice had 95% knockdown of Nox4 expression in the femoral shafts. For mice on regular chow, only whole-body Nox4 knockout mice had clearly increased cortical thickness and bone mineral density in the tibiae. When chronically fed a liquid diet with and without ethanol, conditional Nox4 knockout mice had slightly reduced dimensions of the cortical and trabecular regions of the tibiae (P < 0.1). The ethanol diet caused a significant reduction in cortical bone area and cortical thickness relative to a control diet without ethanol (P < 0.05). The ethanol diet further reduced gene expression of Frizzled related protein (Frzb), myosin heavy chain 3, and several genes encoding collagen and other major structural bone proteins (P < 0.05), whereas the Nox4 genotype had no effects on these genes. In conclusion, Nox4 expression from both mesenchymal and nonmesenchymal cell lineages appears to exert subtle effects on bone. However, chronic ethanol feeding reduces cortical bone mass and cortical gene expression of major structural bone proteins in a Nox4-independent manner.

SIGNIFICANCE STATEMENT Excessive alcohol intake contributes to osteopenia and osteoporosis, with oxidative stress caused by the activity of NADPH oxidases hypothesized to be a mediator. We tested the role of NADPH oxidase (Nox) 4 in osteoblast precursors in the long bones of mice with a conditional Nox4 knockout model. We found that Nox4 exerted effects independent of alcohol intake, and ethanol effects on bone were Nox4-independent.

Footnotes

    • Received December 3, 2019.
    • Accepted March 23, 2020.
  • This work was supported by National Institutes of Health grants National Institute on Alcohol Abuse and Alcoholism R37 [AA018282] (to M.J.R.), National Institute on Alcohol Abuse and Alcoholism F32 [AA026480] (to J.W.), National Institute on Alcohol Abuse and Alcoholism [5T35AA021097 07] (to A.C.R.), and Postbaccalaureate Research Education Program [R25GM12189] (A.W.).

  • The authors declare that they have no conflicts of interest.

  • https://doi.org/10.1124/jpet.119.264374.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 373 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 373, Issue 3
1 Jun 2020
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Research ArticleToxicology

Independent Effects of Nox4 and Ethanol on Bone Biology

Kim B. Pedersen, Michelle L. Osborn, Alex C. Robertson, Ashlee E. Williams, James Watt, Alexandra Denys, Katrin Schröder and Martin J. Ronis
Journal of Pharmacology and Experimental Therapeutics June 1, 2020, 373 (3) 337-346; DOI: https://doi.org/10.1124/jpet.119.264374

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Research ArticleToxicology

Independent Effects of Nox4 and Ethanol on Bone Biology

Kim B. Pedersen, Michelle L. Osborn, Alex C. Robertson, Ashlee E. Williams, James Watt, Alexandra Denys, Katrin Schröder and Martin J. Ronis
Journal of Pharmacology and Experimental Therapeutics June 1, 2020, 373 (3) 337-346; DOI: https://doi.org/10.1124/jpet.119.264374
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