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

Edek A.J. Williams, Veronique Douard, Keiichiro Sugimoto, Hiroshi Inui, Fabienne Devime, Xufei Zhang, Kunihiro Kishida, Ronaldo P. Ferraris, J. Christopher Fritton

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Pages (from-to)541-552
Number of pages12
JournalCalcified Tissue International
Volume106
Issue number5
DOIs
StatePublished - 1 May 2020
Externally publishedYes

Keywords

  • Cyp24b1
  • Cyp27a1
  • Fructose
  • Ketohexokinase

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