| Author |
Terashita S, Yahara Y, Kim JD, Mizutani A, Uchida H, Yaku K, Yamashita M, Imai C, Nakagawa T.
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| Abstract |
Glutamine is a conditionally essential amino acid, and glutaminase 1 (GLS1) catalyzes its conversion to glutamate, which supports cellular energy metabolism and biosynthetic processes. GLS1 has been implicated in osteoclast differentiation in vitro; however, its physiological role in bone homeostasis remains incompletely understood. In this study, we generated Tnfrsf11aCre; Gls1flox/flox (cKO) mice to conditionally delete Gls1 in osteoclast-lineage cells and investigated its function in skeletal homeostasis. These mice exhibited reduced bone mass due to impaired osteoclast activity and decreased osteoblast numbers, suggesting disrupted bone remodeling dynamics. In vitro analyses revealed that Gls1-deficient osteoclasts displayed impaired differentiation and diminished bone resorption capacity, accompanied by significantly reduced intracellular levels of glutamate and α-ketoglutarate. In contrast, osteoblast function was preserved under monoculture and co-culture with osteoclasts, indicating that the in vivo reduction in osteoblast numbers was not due to intrinsic osteoblast dysfunction. While cKO mice appeared phenotypically normal at birth, they developed severe postnatal growth retardation and hypoglycemia, with elevated serum 3-hydroxybutyric acid levels at two weeks of age, indicative of systemic metabolic abnormalities. Since Tnfrsf11a is expressed not only in osteoclasts and their precursors but also in tissue-resident macrophages throughout the body, GLS1 deficiency in these cells may have contributed to postnatal nutritional deficits, leading to systemic growth impairments and compromised skeletal development.
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