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The Effect of Ethanol Consumption on Composition and Morphology of Femur Cortical Bone in Wild-Type and ALDH2*2-Homozygous Mice

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Abstract

ALDH2 inactivating mutation (ALDH2*2) is the most abundant mutation leading to bone morphological aberration. Osteoporosis has long been associated with changes in bone biomaterial in elderly populations. Such changes can be exacerbated with elevated ethanol consumption and in subjects with impaired ethanol metabolism, such as carriers of aldehyde dehydrogenase 2 (ALDH2)-deficient gene, ALDH2*2. So far, little is known about bone compositional changes besides a decrease in mineralization. Raman spectroscopic imaging has been utilized to study the changes in overall composition of C57BL/6 female femur bone sections, as well as in compound spatial distribution. Raman maps of bone sections were analyzed using multilinear regression with these four isolated components, resulting in maps of their relative distribution. A 15-week treatment of both wild-type (WT) and ALDH2*2/*2 mice with 20% ethanol in the drinking water resulted in a significantly lower mineral content (p < 0.05) in the bones. There was no significant change in mineral and collagen content due to the mutation alone (p > 0.4). Highly localized islets of elongated adipose tissue were observed on most maps. Elevated fat content was found in ALDH2*2 knock-in mice consuming ethanol (p < 0.0001) and this effect appeared cumulative. This work conclusively demonstrates that that osteocytes in femurs of older female mice accumulate fat, as has been previously theorized, and that fat accumulation is likely modulated by levels of acetaldehyde, the ethanol metabolite.

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Acknowledgements

Supported in part by CFRI Elizabeth Nash Memorial Fellowship 2015EN01 to AVM, NIH Grants T32 GM089626 and T32 DK 098132 to LDVW, RO1 AA18332 to LJG, and the MERIT Award R37AA11147 to DM-R. We thank Dr. Siyeon Rhee for help with editing the manuscript.

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Authors and Affiliations

  1. Biomaterials and Advanced Drug Delivery Laboratory, Stanford Medical School, Stanford, CA, 94305, USA

    Andrey V. Malkovskiy & Jayakumar Rajadas

  2. Department of Chemical and Systems Biology, Stanford Medical School, Stanford, CA, 94305, USA

    Andrey V. Malkovskiy, Lauren D. Van Wassenhove, Che-Hong Chen & Daria Mochly-Rosen

  3. Department of Microbiology and Immunology, Baxter Laboratory in Stem Cell Biology, Stanford Medical School, Stanford, CA, 94305, USA

    Yury Goltsev

  4. Department of Pharmacology, Weill Cornell Medical College, New York, NY, 10065, USA

    Kwame Osei-Sarfo & Lorraine J. Gudas

  5. Department of Biomedical Data Science, Stanford Medical School, Stanford, CA, 94305, USA

    Bradley Efron

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  1. Andrey V. Malkovskiy
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Correspondence to Andrey V. Malkovskiy or Jayakumar Rajadas.

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Conflict of interest

Dr. Mochly-Rosen reports filing patents related to ALDH2*2 and acetaldehyde metabolism, that were licensed to Foresee, a company she consults. However, none of the work was supported by or is in collaboration with the company. The other authors have no competing interests.

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Mice were treated according to the Administrative Panel on Laboratory Animal Care (APLAC) guidelines, at Weill Cornell Medical College of Cornell University.

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Malkovskiy, A.V., Van Wassenhove, L.D., Goltsev, Y. et al. The Effect of Ethanol Consumption on Composition and Morphology of Femur Cortical Bone in Wild-Type and ALDH2*2-Homozygous Mice. Calcif Tissue Int 108, 265–276 (2021). https://doi.org/10.1007/s00223-020-00769-1

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