2. Academic Validation
  3. Glutaminolysis provides nucleotides and amino acids to regulate osteoclast differentiation in mice

Glutaminolysis provides nucleotides and amino acids to regulate osteoclast differentiation in mice

  • EMBO Rep. 2024 Oct;25(10):4515-4541. doi: 10.1038/s44319-024-00255-x.
Guoli Hu 1,  Yilin Yu 1,  Yinshi Ren 2 3,  Robert J Tower 4 5,  Guo-Fang Zhang 6 7,  Courtney M Karner 8 9
Affiliations

Affiliations

  • 1 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 2 Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX, 75219, USA.
  • 3 Department of Orthopedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 4 Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 5 Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 6 Department of Medicine, Division of Endocrinology, Metabolism Nutrition, Duke University Medical Center, Durham, NC, 27701, USA.
  • 7 Sarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, 27701, USA.
  • 8 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. Courtney.Karner@UTSouthwestern.edu.
  • 9 Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA. Courtney.Karner@UTSouthwestern.edu.
PMID: 39271775 DOI: 10.1038/s44319-024-00255-x
Abstract

Osteoclasts are bone resorbing cells that are essential to maintain skeletal integrity and function. While many of the growth factors and molecular signals that govern osteoclastogenesis are well studied, how the metabolome changes during osteoclastogenesis is unknown. Using a multifaceted approach, we identified a metabolomic signature of osteoclast differentiation consisting of increased amino acid and nucleotide metabolism. Maintenance of the osteoclast metabolic signature is governed by elevated glutaminolysis. Mechanistically, glutaminolysis provides Amino acids and nucleotides which are essential for osteoclast differentiation and bone resorption in vitro. Genetic experiments in mice found that glutaminolysis is essential for osteoclastogenesis and bone resorption in vivo. Highlighting the therapeutic implications of these findings, inhibiting glutaminolysis using CB-839 prevented ovariectomy induced bone loss in mice. Collectively, our data provide strong genetic and pharmacological evidence that glutaminolysis is essential to regulate osteoclast metabolism, promote osteoclastogenesis and modulate bone resorption in mice.

Keywords

Amino Acids; Glutaminolysis; Nucleotides; Osteoclast; Osteoporosis.

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