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O-GlcNAcylation mediates Wnt-stimulated bone formation by rewiring aerobic glycolysis

Chengjia You1, Fangyuan Shen1, Puying Yang1

  • 1State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

EMBO Reports
|September 10, 2024
PubMed

Insights

O-GlcNAcylation is crucial for bone growth and fracture healing by regulating Wnt signaling. This study reveals how O-GlcNAcylation enhances glucose metabolism, promoting osteoblast function and bone anabolism.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Bone Biology

Background:

  • Wnt signaling is a key target for osteoporosis therapies.
  • Sclerostin-neutralizing antibodies enhance bone mass.
  • Cellular mechanisms of Wnt-induced osteogenesis require further investigation.

Purpose of the Study:

  • To investigate the role of O-GlcNAcylation in Wnt signaling-mediated osteogenesis.
  • To elucidate the molecular mechanisms linking Wnt signaling, O-GlcNAcylation, and bone metabolism.

Main Methods:

  • In vitro and in vivo studies using Wnt3a stimulation.
  • Genetic ablation of O-GlcNAcylation in osteoblast-lineage cells.
  • Analysis of protein modification, glucose metabolism, and bone formation markers.

Main Results:

  • Wnt3a rapidly induces O-GlcNAcylation via the Ca2+-PKA-Gfat1 axis and increases it with prolonged stimulation.
  • O-GlcNAcylation is essential for osteoblastogenesis in vitro and in vivo.
  • Genetic deletion of O-GlcNAcylation impairs Wnt-stimulated bone formation and fracture healing.
  • Wnt3a-induced O-GlcNAcylation at PDK1 stabilizes the protein, enhancing glycolysis and osteogenesis.

Conclusions:

  • O-GlcNAcylation is indispensable for Wnt-induced osteogenesis and bone anabolism.
  • O-GlcNAcylation regulates Wnt-induced glucose metabolism through PDK1 stabilization.
  • Targeting O-GlcNAcylation may offer novel therapeutic strategies for osteoporosis.
Keywords:
Bone FormationFracture HealingGlucose MetabolismO-GlcNAcylationWnt

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