Osteoblast-intrinsic defect in glucose metabolism impairs bone formation in type II diabetic male mice
- Children's Hospital of Philadelphia, United States
- Princeton University, United States
- 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)
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Osteoblast-intrinsic defect in glucose metabolism impairs bone formation in type II diabetic male miceNCBI Gene Expression Omnibus, GSE221936.
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Data from: Osteoblast-intrinsic defect in glucose metabolism impairs bone formation in type II diabetic male miceDryad Digital Repository, doi:10.5061/dryad.s7h44j1bc.
Article and author information
Author details
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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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
