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Lactate Efflux From Intervertebral Disc Cells Is Required for Maintenance of Spine Health.

Authors
  • Silagi, Elizabeth S1
  • Novais, Emanuel J1
  • Bisetto, Sara2
  • Telonis, Aristeidis G3
  • Snuggs, Joseph4
  • Le Maitre, Christine L4
  • Qiu, Yunping5
  • Kurland, Irwin J5
  • Shapiro, Irving M1
  • Philp, Nancy J2
  • Risbud, Makarand V1
  • 1 Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, PA, USA.
  • 2 Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
  • 3 Computational Medicine Center, Sidney Kimmel Medical College Thomas Jefferson University, Philadelphia, PA, USA.
  • 4 Biomolecular Sciences Research Centre Sheffield Hallam University, Sheffield, UK.
  • 5 Department of Medicine, Fleischer Institute for Diabetes and Metabolism Albert Einstein College of Medicine, Bronx, NY, USA.
Type
Published Article
Journal
Journal of Bone and Mineral Research
Publisher
Wiley (John Wiley & Sons)
Publication Date
Mar 01, 2020
Volume
35
Issue
3
Pages
550–570
Identifiers
DOI: 10.1002/jbmr.3908
PMID: 31692093
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Maintenance of glycolytic metabolism is postulated to be required for health of the spinal column. In the hypoxic tissues of the intervertebral disc and glycolytic cells of vertebral bone, glucose is metabolized into pyruvate for ATP generation and reduced to lactate to sustain redox balance. The rise in intracellular H+ /lactate concentrations are balanced by plasma-membrane monocarboxylate transporters (MCTs). Using MCT4 null mice and human tissue samples, complemented with genetic and metabolic approaches, we determine that H+ /lactate efflux is critical for maintenance of disc and vertebral bone health. Mechanistically, MCT4 maintains glycolytic and tricarboxylic acid (TCA) cycle flux and intracellular pH homeostasis in the nucleus pulposus compartment of the disc, where hypoxia-inducible factor 1α (HIF-1α) directly activates an intronic enhancer in SLC16A3. Ultimately, our results provide support for research into lactate as a diagnostic biomarker for chronic, painful, disc degeneration. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

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