The DOI matches its Crossref record; 68 of the 69 references it cites were found in a registry or an index.
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]
Experimental — accuracy not yet measuredIn the citing paper
“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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Cites
DeBerardinis, R. J., Mancuso, A., Daikhin, E., Nissim, I., Yudkoff, M., Wehrli, S., & Thompson, C. B. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709747104 · Cited by 2,622
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Metallo, C. M., Gameiro, P. A., Bell, E. L., Mattaini, K. R., Yang, J., Hiller, K., Jewell, C. M., Johnson, Z. R., Irvine, D. J., Guarente, L., et al. (2012) · Nature · doi:10.1038/nature10602 · Cited by 1,791
Glutamine addiction: a new therapeutic target in cancer
Wise, D. R., & Thompson, C. B. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.05.003 · Cited by 1,770 · cited 2×
“Second, SSC may be addicted to glutamine metabolism to support proliferation similar to some cancer cells (Wise and Thompson, 2010).”
BackgroundOsteogenesis in transplants of bone marrow cells
Friedenstein, A. J., Piatetzky-Shapiro, I. I., & Kv, P. (1966) · Development · doi:10.1242/dev.16.3.381 · Cited by 1,675
Nutrition Needs of Mammalian Cells in Tissue Culture
Eagle, H. (1955) · Science · doi:10.1126/science.122.3168.501 · Cited by 1,619 · cited 1×
“Glutamine has long been recognized as an important nutrient in proliferating cells in culture (Eagle, et al., 1956; Eagle, 1955).”
BackgroundBirsoy, K., Wang, T., Chen, W. W., Freinkman, E., Abu-Remaileh, M., & Sabatini, D. M. (2015) · Cell · doi:10.1016/j.cell.2015.07.016 · Cited by 1,388
Zhou, B. O., Yue, R., Murphy, M. M., Peyer, J. G., & Morrison, S. J. (2014) · Cell Stem Cell · doi:10.1016/j.stem.2014.06.008 · Cited by 1,381
CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance
Greenbaum, A. M., Hsu, Y.-M. S., Day, R. B., Schuettpelz, L. G., Christopher, M. J., Borgerding, J. N., Nagasawa, T., & Link, D. C. (2013) · Nature · doi:10.1038/nature11926 · Cited by 1,372
Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches
Ding, L., & Morrison, S. J. (2013) · Nature · doi:10.1038/nature11885 · Cited by 1,349 · cited 2×
“Recent studies have demonstrated SSC arise postnatally, are tightly associated with the vasculature in vivo and can be targeted in mouse using various Cre lines including Prx1Cre and LeprCre (Mizoguchi, et al., 2014; Zhou, et al., 2014; Ding and Morrison, 2013; Greenbaum, et al., 2013).”
BackgroundReductive carboxylation supports growth in tumour cells with defective mitochondria
Mullen, A. R., Wheaton, W. W., Jin, E. S., Chen, P.-H., Sullivan, L. B., Cheng, T., Yang, Y., Linehan, W. M., Chandel, N. S., & DeBerardinis, R. J. (2012) · Nature · doi:10.1038/nature10642 · Cited by 1,328
Cited by
Sorted by citations
Glutamine reliance in cell metabolism
Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00504-8 · Cited by 1,021
Self-citationThe role of osteoblasts in energy homeostasis
Dirckx, N., Moorer, M. C., Clemens, T. L., & Riddle, R. C. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0246-y · Cited by 292
The Role of Osteoclast Energy Metabolism in the Occurrence and Development of Osteoporosis
Da, W., Tao, L., & Zhu, Y. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.675385 · Cited by 185
“Glutamine is decomposed to form a-ketoglutarate, which enters the tricarboxylic acid cycle and is converted to citrate through oxidation (118, 119).”
BackgroundXiong, Y., Chen, L., Yan, C., Zhou, W., Tao, Y., Sun, Y. T., Cao, F., Xue, H., Hu, Y., Chen, D., et al. (2020) · Journal of Nanobiotechnology · doi:10.1186/s12951-020-00622-5 · Cited by 162
RetractedBehera, J., Kumar, A., Voor, M. J., & Tyagi, N. (2021) · Theranostics · doi:10.7150/thno.58410 · Cited by 148
“Both alkaline phosphatase (ALP) staining, and alizarin red (ARS) staining were performed at 6 and 21 days, as previously described protocol [1, 40].”
Method
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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