Osteoblast-intrinsic defect in glucose metabolism impairs bone formation in type II diabetic male mice

  1. Fangfang Song
  2. Won Dong Lee
  3. Tyler Marmo
  4. Xing Ji
  5. Chao Song
  6. Xueyang Liao
  7. Rebecca Seeley
  8. Lutian Yao
  9. Haoran Liu
  10. Fanxin Long  Is a corresponding author
  1. Children's Hospital of Philadelphia, United States
  2. Princeton University, United States
  3. New Jersey Institute of Technology, United States

Abstract

Skeletal fragility is associated with type 2 diabetes mellitus (T2D), but the underlying mechanism is not well understood. Here, in a mouse model for youth-onset T2D, we show that both trabecular and cortical bone mass are reduced due to diminished osteoblast activity. Stable isotope tracing in vivo with 13C-glucose demonstrates that both glycolysis and glucose fueling of the TCA cycle are impaired in diabetic bones. Similarly, Seahorse assays show suppression of both glycolysis and oxidative phosphorylation by diabetes in bone marrow mesenchymal cells as a whole, whereas single-cell RNA sequencing reveals distinct modes of metabolic dysregulation among the subpopulations. Metformin not only promotes glycolysis and osteoblast differentiation in vitro, but also improves bone mass in diabetic mice. Finally, osteoblast-specific overexpression of either Hif1a, a general inducer of glycolysis, or Pfkfb3 which stimulates a specific step in glycolysis, averts bone loss in T2D mice. The study identifies osteoblast-intrinsic defects in glucose metabolism as an underlying cause of diabetic osteopenia, which may be targeted therapeutically.

Data availability

scRNA-seq data has been deposited in GEO under access code GSE221936All source data for figures and the R script for scRNA analyses have been uploaded to Dryad (doi:10.5061/dryad.s7h44j1bc)

The following data sets were generated

Article and author information

Author details

  1. Fangfang Song

    Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9465-6083
  2. Won Dong Lee

    Lewis Sigler Institute for Integrative Genomics, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2344-171X
  3. Tyler Marmo

    Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Xing Ji

    Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Chao Song

    Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Xueyang Liao

    Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Rebecca Seeley

    Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Lutian Yao

    Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Haoran Liu

    Department of Computer Science, New Jersey Institute of Technology, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Fanxin Long

    Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, United States
    For correspondence
    longf1@chop.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9785-5379

Funding

National Institutes of Health (DK125498)

  • Fanxin Long

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal studies were conducted in strict accordance with the protocols approved by the Institutional Animal Care and Use Committee (IACUC) at Children's Hospital of Philadelphia. The IACUC approval number is IAC 21-001296.

Copyright

© 2023, Song et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Fangfang Song
  2. Won Dong Lee
  3. Tyler Marmo
  4. Xing Ji
  5. Chao Song
  6. Xueyang Liao
  7. Rebecca Seeley
  8. Lutian Yao
  9. Haoran Liu
  10. Fanxin Long
(2023)
Osteoblast-intrinsic defect in glucose metabolism impairs bone formation in type II diabetic male mice
eLife 12:e85714.
https://doi.org/10.7554/eLife.85714

Share this article

https://doi.org/10.7554/eLife.85714

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