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Cell Metab. 2019 Apr 2;29(4):966-978.e4. doi: 10.1016/j.cmet.2019.01.016. Epub 2019 Feb 14.

Glutamine Metabolism Regulates Proliferation and Lineage Allocation in Skeletal Stem Cells.

Author information

1
Department of Orthopaedic Surgery, Duke Orthopaedic Cellular, Developmental, and Genome Laboratories, Duke University School of Medicine, Durham, NC 27710, USA.
2
Sarah W. Stedman Nutrition and Metabolism Center & Duke Molecular Physiology Institute, Duke University Medical Center, 300 North Duke Street, Durham, NC 27701, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27701, USA.
3
Department of Orthopaedic Surgery, Duke Orthopaedic Cellular, Developmental, and Genome Laboratories, Duke University School of Medicine, Durham, NC 27710, USA; Department of Cell Biology, Duke University, Durham, NC 27710, USA.
4
Department of Orthopaedic Surgery, Duke Orthopaedic Cellular, Developmental, and Genome Laboratories, Duke University School of Medicine, Durham, NC 27710, USA; Department of Cell Biology, Duke University, Durham, NC 27710, USA. Electronic address: courtney.karner@duke.edu.

Abstract

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.

KEYWORDS:

alpha ketoglutarate; glutaminase; glutamine metabolism; lineage specification; osteoporosis; skeletal stem cell

PMID:
30773468
DOI:
10.1016/j.cmet.2019.01.016

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