Zhang Lu, Qi Bao, Li Yanpeng, Liang Xiao, Zhang Zifang, Yang Tao, Jia Shu, Gao Xu, Chen Shang, Jiao Guangjun, Li Yangyang, Zhou Hongming, Chen Yunzhen, Li Yanming, Zhang Bin, Li Gang, Meng Chunyang
Department of Spine Surgery, Affiliated Hospital of Jining Medical University, Jining, 272029, China.
Postdoctoral Mobile Station of Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
Cell Death Differ. 2025 Jul 11. doi: 10.1038/s41418-025-01543-2.
The abnormal osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is an important cause of senile osteoporosis (SOP). Glutamine synthetase (GLUL) is a key enzyme in glutamine biosynthesis; however, its functional role in SOP remains unclear. Here, we found that GLUL expression was downregulated in the BMSCs of SOP patients. Mice with BMSC-specific Glul-knockout (KO) exhibited dysplasia of the skull and phalanges and osteoporosis due to disordered osteogenic differentiation. Mechanistically, GLUL competitively bound to the Tripartite Motif Containing 25 (TRIM25) SPRY subunit, reduced the ubiquitin-mediated degradation of UDP-N-acetylglucosamine pyrophosphorylase 1 (UAP1) and increased the synthesis of uridine 5-diphosphate N-acetylglucosamine (UDP-GlcNAc), thereby regulating the O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) of serine 296 residues and increasing Forkhead Box O3 (FOXO3) stability to reduce oxidative stress. Moreover, blocking the O-GlcNAcylation of FOXO3 at Ser296 inhibited osteogenic differentiation. Finally, GLUL supplementation specifically in BMSCs slowed bone loss in SOP model mice. Overall, our study suggests that GLUL plays an important role in regulating osteogenic differentiation and bone development, which may have implications for SOP treatment. Schematic illustration of the molecular mechanism by which GLUL mediates FOXO3 O-GlcNAcylation to regulate the osteogenic differentiation of BMSCs and senile osteoporosis. The graphical abstract was created by figdraw2.0.
骨髓间充质干细胞（BMSCs）的异常成骨分化是老年性骨质疏松症（SOP）的重要原因。谷氨酰胺合成酶（GLUL）是谷氨酰胺生物合成中的关键酶；然而，其在SOP中的功能作用仍不清楚。在这里，我们发现SOP患者的BMSCs中GLUL表达下调。BMSC特异性Glul基因敲除（KO）小鼠由于成骨分化紊乱而出现颅骨和指骨发育异常以及骨质疏松。机制上，GLUL与含三联基序蛋白25（TRIM25）的SPRY亚基竞争性结合，减少泛素介导的UDP-N-乙酰葡糖胺焦磷酸化酶1（UAP1）的降解，并增加尿苷5-二磷酸N-乙酰葡糖胺（UDP-GlcNAc）的合成，从而调节丝氨酸296残基的O-连接β-N-乙酰葡糖胺修饰（O-GlcNAcylation）并增加叉头框O3（FOXO3）的稳定性以降低氧化应激。此外，阻断FOXO3第296位丝氨酸的O-GlcNAcylation会抑制成骨分化。最后，特异性地在BMSCs中补充GLUL可减缓SOP模型小鼠的骨质流失。总体而言，我们的研究表明GLUL在调节成骨分化和骨骼发育中起重要作用，这可能对SOP治疗有启示意义。GLUL介导FOXO3的O-GlcNAcylation以调节BMSCs的成骨分化和老年性骨质疏松症的分子机制示意图。图形摘要由figdraw2.0创建。
