State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Department of Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
EMBO Rep. 2024 Oct;25(10):4465-4487. doi: 10.1038/s44319-024-00237-z. Epub 2024 Sep 10.
Wnt signaling is an important target for anabolic therapies in osteoporosis. A sclerostin-neutralizing antibody (Scl-Ab), that blocks the Wnt signaling inhibitor (sclerostin), has been shown to promote bone mass in animal models and clinical studies. However, the cellular mechanisms by which Wnt signaling promotes osteogenesis remain to be further investigated. O-GlcNAcylation, a dynamic post-translational modification of proteins, controls multiple critical biological processes including transcription, translation, and cell fate determination. Here, we report that Wnt3a either induces O-GlcNAcylation rapidly via the Ca-PKA-Gfat1 axis, or increases it in a Wnt-β-catenin-dependent manner following prolonged stimulation. Importantly, we find O-GlcNAcylation indispensable for osteoblastogenesis both in vivo and in vitro. Genetic ablation of O-GlcNAcylation in the osteoblast-lineage diminishes bone formation and delays bone fracture healing in response to Wnt stimulation in vivo. Mechanistically, Wnt3a induces O-GlcNAcylation at Serine 174 of PDK1 to stabilize the protein, resulting in increased glycolysis and osteogenesis. These findings highlight O-GlcNAcylation as an important mechanism regulating Wnt-induced glucose metabolism and bone anabolism.
Wnt 信号是骨质疏松症中合成代谢治疗的重要靶点。一种骨硬化蛋白中和抗体（Scl-Ab），可以阻断 Wnt 信号抑制剂（骨硬化蛋白），已被证明可促进动物模型和临床研究中的骨量。然而，Wnt 信号促进成骨的细胞机制仍有待进一步研究。O-GlcNAc 化是蛋白质的一种动态翻译后修饰，控制着多种关键的生物学过程，包括转录、翻译和细胞命运决定。在这里，我们报告 Wnt3a 通过 Ca-PKA-Gfat1 轴快速诱导 O-GlcNAc 化，或者在延长刺激后以 Wnt-β-catenin 依赖的方式增加 O-GlcNAc 化。重要的是，我们发现 O-GlcNAc 化在体内和体外的成骨细胞分化中都是必不可少的。在成骨细胞谱系中遗传敲除 O-GlcNAc 化会减少骨形成，并延迟对体内 Wnt 刺激的骨骨折愈合。在机制上，Wnt3a 在 PDK1 的丝氨酸 174 处诱导 O-GlcNAc 化以稳定蛋白，从而导致糖酵解和成骨增加。这些发现强调了 O-GlcNAc 化作为调节 Wnt 诱导的葡萄糖代谢和骨合成代谢的重要机制。
