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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. \u00a9 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).<\/jats:p>","DOI":"10.1002\/jbmr.4219","type":"journal-article","created":{"date-parts":[[2020,11,30]],"date-time":"2020-11-30T14:57:19Z","timestamp":1606748239000},"page":"604-616","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Glutamine Metabolism in Osteoprogenitors Is Required for Bone Mass Accrual and PTH-Induced Bone Anabolism in Male Mice"],"prefix":"10.1093","volume":"36","author":[{"given":"Steve","family":"Stegen","sequence":"first","affiliation":[{"name":"Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism, and Ageing KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire-Sophie","family":"Devignes","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism, and Ageing KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Torrekens","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism, and Ageing KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riet","family":"Van Looveren","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism, and Ageing KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Carmeliet","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center Sun Yat-Sen University Guangzhou China"},{"name":"Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute KU Leuven Leuven Belgium"},{"name":"Laboratory of Angiogenesis and Vascular Metabolism VIB Center for Cancer Biology Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8324-4462","authenticated-orcid":false,"given":"Geert","family":"Carmeliet","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism, and Ageing KU Leuven Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,11,30]]},"reference":[{"key":"2024012713514043300_jbmr4219-bib-0001","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/bonekey.2013.215","article-title":"Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit","volume":"3","author":"Sims","year":"2014","journal-title":"Bonekey 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