2. Academic Validation
  3. GLUL mediates FOXO3 O-GlcNAcylation to regulate the osteogenic differentiation of BMSCs and senile osteoporosis

GLUL mediates FOXO3 O-GlcNAcylation to regulate the osteogenic differentiation of BMSCs and senile osteoporosis

  • Cell Death Differ. 2025 Jul 11. doi: 10.1038/s41418-025-01543-2.
Lu Zhang 1 2 3 4,  Bao Qi 1 3 4,  Yanpeng Li 1 3 4,  Xiao Liang 1 3 4,  Zifang Zhang 2 5,  Tao Yang 1 3 4 6,  Shu Jia 1 2 3 4,  Xu Gao 1 2 3 4,  Shang Chen 1 2 3 4,  Guangjun Jiao 7,  Yangyang Li 8,  Hongming Zhou 9 10,  Yunzhen Chen 7,  Yanming Li 1 3,  Bin Zhang 3 11,  Gang Li 2 12,  Chunyang Meng 13 14 15
Affiliations

Affiliations

  • 1 Department of Spine Surgery, Affiliated Hospital of Jining Medical University, Jining, 272029, China.
  • 2 Postdoctoral Mobile Station of Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
  • 3 Key laboratory of cell and biomedical Technology of Shandong Province, Affiliated Hospital of Jining Medical University, Jining, 272000, China.
  • 4 Clinical Research Team of Spine & Spinal Cord Diseases, Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, 272000, China.
  • 5 Department of Spine Center, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China.
  • 6 Qingdao Medical College of Qingdao University, Qingdao, 266003, China.
  • 7 Department of Spine Surgery, Qilu Hospital of Shandong University, Jinan, 250012, China.
  • 8 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 9 Department of Orthopaedics, Linyi Central Hospital, Linyi, 276401, China.
  • 10 Department of Spine Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
  • 11 Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272000, China.
  • 12 Department of Orthopaedics, Shandong University of Traditional Chinese Medicine, Jinan, 250014, China.
  • 13 Department of Spine Surgery, Affiliated Hospital of Jining Medical University, Jining, 272029, China. mengchunyang1600@mail.jnmc.edu.cn.
  • 14 Key laboratory of cell and biomedical Technology of Shandong Province, Affiliated Hospital of Jining Medical University, Jining, 272000, China. mengchunyang1600@mail.jnmc.edu.cn.
  • 15 Clinical Research Team of Spine & Spinal Cord Diseases, Medical Research Center, Affiliated Hospital of Jining Medical University, Jining, 272000, China. mengchunyang1600@mail.jnmc.edu.cn.
PMID: 40646162 DOI: 10.1038/s41418-025-01543-2
Abstract

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z