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Bone Growth is Influenced by Fructose in Adolescent Male Mice Lacking Ketohexokinase (KHK)

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Abstract

Fructose is metabolized in the cytoplasm by the enzyme ketohexokinase (KHK), and excessive consumption may affect bone health. Previous work in calcium-restricted, growing mice demonstrated that fructose disrupted intestinal calcium transport. Thus, we hypothesized that the observed effects on bone were dependent on fructose metabolism and took advantage of a KHK knockout (KO) model to assess direct effects of high plasma fructose on the long bones of growing mice. Four groups (n = 12) of 4-week-old, male, C57Bl/6 background, congenic mice with intact KHK (wild-type, WT) or global knockout of both isoforms of KHK-A/C (KHK-KO), were fed 20% glucose (control diet) or fructose for 8 weeks. Dietary fructose increased by 40-fold plasma fructose in KHK-KO compared to the other three groups (p < 0.05). Obesity (no differences in epididymal fat or body weight) or altered insulin was not observed in either genotype. The femurs of KHK-KO mice with the highest levels of plasma fructose were shorter (2%). Surprisingly, despite the long-term blockade of KHK, fructose feeding resulted in greater bone mineral density, percent volume, and number of trabeculae as measured by µCT in the distal femur of KHK-KO. Moreover, higher plasma fructose concentrations correlated with greater trabecular bone volume, greater work-to-fracture in three-point bending of the femur mid-shaft, and greater plasma sclerostin. Since the metabolism of fructose is severely inhibited in the KHK-KO condition, our data suggest mechanism(s) that alter bone growth may be related to the plasma concentration of fructose.

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Acknowledgements

Publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH Award Numbers: AR063351, AR074670). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We thank Drs. Joseph Geissler, George Pellegrino, Stephen Flowers, Patricia Buckendahl, and Chirag Patel, as well as Brian Canter, Mayuri Kinkhabwala, Juby Roy, David Sadegh, Timothy Ngoge, Alexander Kheshvadjian, Joe Lumuti, and Luke Fritzky for technical assistance.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Graduate School, Rutgers University, New Brunswick, NJ, USA

    Edek A. J. Williams & J. Christopher Fritton

  2. MICALIS Institute, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France

    Veronique Douard, Fabienne Devime & Xufei Zhang

  3. Research and Development Center, Nagaoka Co. Ltd, Ibaraki, Osaka, Japan

    Keiichiro Sugimoto

  4. Center for Research and Development of Bioresources & Department of Clinical Nutrition, College of Health and Human Sciences, Osaka Prefecture University, Habikino, Osaka, Japan

    Hiroshi Inui

  5. Department of Science and Technology On Food Safety, Kindai University, Wakayama, Japan

    Kunihiro Kishida

  6. Department of Pharmacology and Physiology, New Jersey Medical School, Rutgers University, Newark, NJ, USA

    Ronaldo P. Ferraris

  7. Departments of Mechanical and Biomedical Engineering, Grove School of Engineering, The City College of New York, 160 Convent Avenue, Steinman Hall T401, New York, NY, 10031, USA

    J. Christopher Fritton

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  1. Edek A. J. Williams
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The manuscript was approved by all authors, whom are solely responsible for the decision to submit for publication. There are no other persons who satisfied the criteria for authorship but are not listed. EW, VD, RF, and JF contributed to study design; EW, KS, HI, FD, XZ, and KK were involved in data collection; EW, VD, RF, and JF performed data analysis and interpretation; EW wrote the first draft; and VD, RF, and JF were involved in critical editing of the final version of the manuscript.

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Correspondence to J. Christopher Fritton.

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Edek A. J. Williams, Veronique Douard, Keiichiro Sugimoto, Hiroshi Inui, Fabienne Devime, Xufei Zhang, Kunihiro Kishida, Ronaldo P. Ferraris, and J. Christopher Fritton declare that they have no conflict of interest.

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Animal care and experimental protocols were approved by the Rutgers Institutional Animal Care and Use Committee (IACUC) and were done in accordance with institutional guidelines and under the supervision of authorized investigators.

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Williams, E.A.J., Douard, V., Sugimoto, K. et al. Bone Growth is Influenced by Fructose in Adolescent Male Mice Lacking Ketohexokinase (KHK). Calcif Tissue Int 106, 541–552 (2020). https://doi.org/10.1007/s00223-020-00663-w

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