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Glutamine Metabolism in Osteoprogenitors Is Required for Bone Mass Accrual and PTH ‐Induced Bone Anabolism in Male Mice
Author(s) -
Stegen Steve,
Devignes ClaireSophie,
Torrekens Sophie,
Van Looveren Riet,
Carmeliet Peter,
Carmeliet Geert
Publication year - 2021
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.4219
Subject(s) - glutamine , anabolism , catabolism , glutaminase , medicine , endocrinology , bone remodeling , metabolism , glutaminolysis , chemistry , biology , biochemistry , amino acid
ABSTRACT Skeletal homeostasis critically depends on the proper anabolic functioning of osteolineage cells. Proliferation and matrix synthesis are highly demanding in terms of biosynthesis and bioenergetics, but the nutritional requirements that support these processes in bone‐forming cells are not fully understood. Here, we show that glutamine metabolism is a major determinant of osteoprogenitor function during bone mass accrual. Genetic inactivation of the rate‐limiting enzyme glutaminase 1 (GLS1) results in decreased postnatal bone mass, caused by impaired biosynthesis and cell survival. Mechanistically, we uncovered that GLS1‐mediated glutamine catabolism supports nucleotide and amino acid synthesis, required for proliferation and matrix production. In addition, glutamine‐derived glutathione prevents accumulation of reactive oxygen species and thereby safeguards cell viability. The pro‐anabolic role of glutamine metabolism was further underscored in a model of parathyroid hormone (PTH)‐induced bone formation. PTH administration increases glutamine uptake and catabolism, and GLS1 deletion fully blunts the PTH‐induced osteoanabolic response. Taken together, our findings indicate that glutamine metabolism in osteoprogenitors is indispensable for bone formation. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).