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Research ArticleToxicology

Vitamin D Supplementation Protects against Bone Loss Associated with Chronic Alcohol Administration in Female Mice

Kelly E. Mercer, Rebecca A. Wynne, Oxana P. Lazarenko, Charles K. Lumpkin, William R. Hogue, Larry J. Suva, Jin-Ran Chen, Andrew Z. Mason, Thomas M. Badger and Martin J. J. Ronis
Journal of Pharmacology and Experimental Therapeutics November 2012, 343 (2) 401-412; DOI: https://doi.org/10.1124/jpet.112.197038
Kelly E. Mercer
Departments of Pharmacology and Toxicology (K.E.M., M.J.J.R.), Pediatrics (C.K.L., J.-R.C., T.M.B., M.J.J.R.), and Orthopaedic Surgery, Center for Orthopaedic Research (W.R.H., L.J.S.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Arkansas Children's Nutrition Center, Little Rock, Arkansas (R.A.W., O.P.L., J.-R.C., T.M.B., M.J.J.R.); and Department of Biological Sciences, California State University, Long Beach, California (A.Z.M.)
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Rebecca A. Wynne
Departments of Pharmacology and Toxicology (K.E.M., M.J.J.R.), Pediatrics (C.K.L., J.-R.C., T.M.B., M.J.J.R.), and Orthopaedic Surgery, Center for Orthopaedic Research (W.R.H., L.J.S.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Arkansas Children's Nutrition Center, Little Rock, Arkansas (R.A.W., O.P.L., J.-R.C., T.M.B., M.J.J.R.); and Department of Biological Sciences, California State University, Long Beach, California (A.Z.M.)
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Oxana P. Lazarenko
Departments of Pharmacology and Toxicology (K.E.M., M.J.J.R.), Pediatrics (C.K.L., J.-R.C., T.M.B., M.J.J.R.), and Orthopaedic Surgery, Center for Orthopaedic Research (W.R.H., L.J.S.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Arkansas Children's Nutrition Center, Little Rock, Arkansas (R.A.W., O.P.L., J.-R.C., T.M.B., M.J.J.R.); and Department of Biological Sciences, California State University, Long Beach, California (A.Z.M.)
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Charles K. Lumpkin
Departments of Pharmacology and Toxicology (K.E.M., M.J.J.R.), Pediatrics (C.K.L., J.-R.C., T.M.B., M.J.J.R.), and Orthopaedic Surgery, Center for Orthopaedic Research (W.R.H., L.J.S.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Arkansas Children's Nutrition Center, Little Rock, Arkansas (R.A.W., O.P.L., J.-R.C., T.M.B., M.J.J.R.); and Department of Biological Sciences, California State University, Long Beach, California (A.Z.M.)
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William R. Hogue
Departments of Pharmacology and Toxicology (K.E.M., M.J.J.R.), Pediatrics (C.K.L., J.-R.C., T.M.B., M.J.J.R.), and Orthopaedic Surgery, Center for Orthopaedic Research (W.R.H., L.J.S.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Arkansas Children's Nutrition Center, Little Rock, Arkansas (R.A.W., O.P.L., J.-R.C., T.M.B., M.J.J.R.); and Department of Biological Sciences, California State University, Long Beach, California (A.Z.M.)
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Larry J. Suva
Departments of Pharmacology and Toxicology (K.E.M., M.J.J.R.), Pediatrics (C.K.L., J.-R.C., T.M.B., M.J.J.R.), and Orthopaedic Surgery, Center for Orthopaedic Research (W.R.H., L.J.S.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Arkansas Children's Nutrition Center, Little Rock, Arkansas (R.A.W., O.P.L., J.-R.C., T.M.B., M.J.J.R.); and Department of Biological Sciences, California State University, Long Beach, California (A.Z.M.)
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Jin-Ran Chen
Departments of Pharmacology and Toxicology (K.E.M., M.J.J.R.), Pediatrics (C.K.L., J.-R.C., T.M.B., M.J.J.R.), and Orthopaedic Surgery, Center for Orthopaedic Research (W.R.H., L.J.S.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Arkansas Children's Nutrition Center, Little Rock, Arkansas (R.A.W., O.P.L., J.-R.C., T.M.B., M.J.J.R.); and Department of Biological Sciences, California State University, Long Beach, California (A.Z.M.)
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Andrew Z. Mason
Departments of Pharmacology and Toxicology (K.E.M., M.J.J.R.), Pediatrics (C.K.L., J.-R.C., T.M.B., M.J.J.R.), and Orthopaedic Surgery, Center for Orthopaedic Research (W.R.H., L.J.S.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Arkansas Children's Nutrition Center, Little Rock, Arkansas (R.A.W., O.P.L., J.-R.C., T.M.B., M.J.J.R.); and Department of Biological Sciences, California State University, Long Beach, California (A.Z.M.)
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Thomas M. Badger
Departments of Pharmacology and Toxicology (K.E.M., M.J.J.R.), Pediatrics (C.K.L., J.-R.C., T.M.B., M.J.J.R.), and Orthopaedic Surgery, Center for Orthopaedic Research (W.R.H., L.J.S.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Arkansas Children's Nutrition Center, Little Rock, Arkansas (R.A.W., O.P.L., J.-R.C., T.M.B., M.J.J.R.); and Department of Biological Sciences, California State University, Long Beach, California (A.Z.M.)
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Martin J. J. Ronis
Departments of Pharmacology and Toxicology (K.E.M., M.J.J.R.), Pediatrics (C.K.L., J.-R.C., T.M.B., M.J.J.R.), and Orthopaedic Surgery, Center for Orthopaedic Research (W.R.H., L.J.S.), University of Arkansas for Medical Sciences, Little Rock, Arkansas; Arkansas Children's Nutrition Center, Little Rock, Arkansas (R.A.W., O.P.L., J.-R.C., T.M.B., M.J.J.R.); and Department of Biological Sciences, California State University, Long Beach, California (A.Z.M.)
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Abstract

Chronic alcohol abuse results in decreased bone mineral density (BMD), which can lead to increased fracture risk. In contrast, low levels of alcohol have been associated with increased BMD in epidemiological studies. Alcohol's toxic skeletal effects have been suggested to involve impaired vitamin D/calcium homeostasis. Therefore, dietary vitamin D supplementation may be beneficial in reducing bone loss associated with chronic alcohol consumption. Six-week-old female C57BL/6J mice were pair-fed ethanol (EtOH)-containing liquid diets (10 or 36% total calories) for 78 days. EtOH exposure at 10% calories had no effects on any measured bone or serum parameter. EtOH consumption at 36% of calories reduced BMD and bone strength (P < 0.05), decreased osteoblastogenesis, increased osteoclastogenesis, suppressed 1,25-hydroxyvitamin D3 [1,25(OH)2D3] serum concentrations (P < 0.05), and increased apoptosis in bone cells compared with pair-fed controls. In a second study, female mice were pair-fed 30% EtOH diets with or without dietary supplementation with vitamin D3 (cholecalciferol; VitD) for 40 days. VitD supplementation in the EtOH diet protected against cortical bone loss, normalized alcohol-induced hypocalcaemia, and suppressed EtOH-induced expression of receptor of nuclear factor-κB ligand mRNA in bone. In vitro, pretreatment of 1,25(OH)2D3 in osteoblastic cells inhibited EtOH-induced apoptosis. In EtOH/VitD mice circulating 1,25(OH)2D3 was lower compared with mice receiving EtOH alone (P < 0.05), suggesting increased sensitivity to feedback control of VitD metabolism in the kidney. These findings suggest dietary VitD supplementation may prevent skeletal toxicity in chronic drinkers by normalizing calcium homeostasis, preventing apoptosis, and suppressing EtOH-induced increases in bone resorption.

Footnotes

  • This work was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grant RO1 AA18282], the Arkansas Children's Hospital Research Institute Lyons Fund; and the Carl L. Nelson Chair in Orthopaedic Creativity, University of Arkansas for Medical Sciences.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.197038.

  • ABBREVIATIONS:

    BMD
    bone mineral density
    EtOH
    ethanol
    TEN
    total enteral nutrition
    VitD
    vitamin D3/cholecalciferol
    25OHD3
    25-hydroxyvitamin D3
    1,25(OH)2D3
    1,25-hydroxyvitamin D3
    PF
    pair-fed
    CT
    computed topography
    μCT
    micro-CT
    ROI
    regions of interest
    TRAP
    tartrate-resistant acid phosphatase
    CTX
    C-terminal telopeptide
    BEC
    blood ethanol concentration
    CV
    coefficient of variation
    PTH
    parathyroid hormone
    BV/TV
    bone volume/tissue volume
    VDR
    vitamin D receptor
    RANKL
    receptor of nuclear factor-κB ligand
    TUNEL
    terminal deoxynucleotidyl transferase dUTP nick-end labeling
    αMEM
    α-minimal essential medium
    FBS
    fetal bovine serum
    ANOVA
    analysis of variance
    PCR
    polymerase chain reaction.

  • Received May 31, 2012.
  • Accepted August 13, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 2
1 Nov 2012
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Research ArticleToxicology

Vitamin D Supplementation Prevents EtOH-Mediated Bone Loss

Kelly E. Mercer, Rebecca A. Wynne, Oxana P. Lazarenko, Charles K. Lumpkin, William R. Hogue, Larry J. Suva, Jin-Ran Chen, Andrew Z. Mason, Thomas M. Badger and Martin J. J. Ronis
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 401-412; DOI: https://doi.org/10.1124/jpet.112.197038

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Research ArticleToxicology

Vitamin D Supplementation Prevents EtOH-Mediated Bone Loss

Kelly E. Mercer, Rebecca A. Wynne, Oxana P. Lazarenko, Charles K. Lumpkin, William R. Hogue, Larry J. Suva, Jin-Ran Chen, Andrew Z. Mason, Thomas M. Badger and Martin J. J. Ronis
Journal of Pharmacology and Experimental Therapeutics November 1, 2012, 343 (2) 401-412; DOI: https://doi.org/10.1124/jpet.112.197038
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