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Glutamine Metabolism Regulates Proliferation and Lineage Allocation in Skeletal Stem Cells
Open accessAbstract
Skeletal stem cells (SSCs) are postulated to provide a continuous supply of osteoblasts throughout life. However, under certain conditions, the SSC population can become incorrectly specified or is not maintained, resulting in reduced osteoblast formation, decreased bone mass, and in severe cases, osteoporosis. Glutamine metabolism has emerged as a critical regulator of many cellular processes in diverse pathologies. The enzyme glutaminase (GLS) deaminates glutamine to form glutamate-the rate-limiting first step in glutamine metabolism. Using genetic and metabolic approaches, we demonstrate GLS and glutamine metabolism are required in SSCs to regulate osteoblast and adipocyte specification and bone formation. Mechanistically, transaminase-dependent α-ketoglutarate production is critical for the proliferation, specification, and differentiation of SSCs. Collectively, these data suggest stimulating GLS activity may provide a therapeutic approach to expand SSCs in aged individuals and enhance osteoblast differentiation and activity to increase bone mass.
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“It has been observed that when osteoblasts are induced to undergo mineralization, glucose alone is inadequate to fulfill their energy needs. The degree of mineralization only increases when cells are provided with glucose and glutamine supplementation [64, 65].”
From Mesenchymal stromal cells in bone marrow niche of patients with multiple myeloma: a double-edged sword (2025) · cites this paper as [65]
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“In skeletal stem cells (SSCs), GLS and glutamine metabolism are required for the regulation of osteoblast and adipocyte specification and physiological bone formation107.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [107]
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Current cutting-edge omics techniques on musculoskeletal tissues and diseases
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“Stable isotope tracing has been particularly fruitful for tracing the fl ux of glucose and several different amino acids during osteoblast differentiation in cultured cells 193,194,197,198,221 and more recently in whole bones in vivo.”
Self-citationThe Amino Acid Sensor Eif2ak4/GCN2 Is Required for Proliferation of Osteoblast Progenitors in Mice
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“known SSPC increase glutamine consumption and require glutamine metabolism to support proliferation,((15)) more broadly, the”
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Regulation of bone marrow mesenchymal stem cell fate by long non-coding RNA
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Role and mechanisms of autophagy in lung metabolism and repair
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“The degree of mineralization only increases when cells are provided with glucose and glutamine supplementation [64, 65].”
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Glutamine-dependent signaling controls pluripotent stem cell fate
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Metabolic crosstalk between stromal and malignant cells in the bone marrow niche
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Alpha-ketoglutarate promotes alveolar bone regeneration by modulating M2 macrophage polarization
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Metadata
- Authors
- Yu, Y., Newman, H., Shen, L., Sharma, D., Hu, G., Mirando, A. J., Zhang, H., Knudsen, E., Zhang, G.-F., Hilton, M. J., & Karner, C. M.
- Affiliations
- Duke University (US)
- Corresponding author
- Karner, Courtney M.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 29
- Issue
- 4
- Pages
- 966-978.e4
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC7062112
- OpenAlex
- W2913128985
- Cited by
- 253
- References
- 69
- Citations by year
- 2026: 26 · 2025: 37 · 2024: 41 · 2023: 38 · 2022: 40 · 2021: 31 · 2020: 34 · 2019: 6
- FWCI
- 9.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (2AR063071, AR071967)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Keywords
- skeletal stem cells, glutamine metabolism, glutaminase, osteogenic differentiation, adipogenesis, lineage specification, cell proliferation, alpha-ketoglutarate, transamination, bone formation, bone mass, osteoporosis, aging, stem cell expansion
- MeSH terms
- Animals, Cells, Cultured, Female, Glutamine, Male, Mice, Inbred Strains, Mass Spectrometry, Muscle, Skeletal, Cell Lineage, Myoblasts, Skeletal, Cell Proliferation, Mice
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