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

IF 6.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

EMBO Reports Pub Date : 2024-09-10 DOI:10.1038/s44319-024-00237-z

Chengjia You,Fangyuan Shen,Puying Yang,Jingyao Cui,Qiaoyue Ren,Moyu Liu,Yujie Hu,Boer Li,Ling Ye,Yu Shi

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引用次数: 0

Abstract

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 Ca2+-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.

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O-GlcNAcylation通过重新连接有氧糖酵解介导Wnt刺激的骨形成。

Wnt 信号是骨质疏松症同化疗法的一个重要靶点。在动物模型和临床研究中，一种能阻断 Wnt 信号抑制剂（硬骨素）的硬骨素中和抗体（Scl-Ab）已被证明能促进骨量。然而，Wnt 信号促进成骨的细胞机制仍有待进一步研究。O-GlcNA酰化是蛋白质的一种动态翻译后修饰，它控制着多种关键的生物过程，包括转录、翻译和细胞命运决定。在此，我们报告了 Wnt3a 通过 Ca2+-PKA-Gfat1 轴快速诱导 O-GlcNAcylation 或在长时间刺激后以 Wnt-β-catenin 依赖性方式增加 O-GlcNAcylation 的情况。重要的是，我们发现 O-GlcNAcylation 对体内和体外成骨细胞的形成都是不可或缺的。遗传性消减成骨细胞系中的 O-GlcNAcylation 会减少骨形成并延迟体内 Wnt 刺激下的骨折愈合。从机理上讲，Wnt3a诱导PDK1丝氨酸174处的O-GlcNAcylation以稳定该蛋白，从而导致糖酵解和骨生成增加。这些发现强调了O-GlcNAcylation是调节Wnt诱导的糖代谢和骨合成代谢的重要机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Reports 生物-生化与分子生物学

CiteScore

11.20

自引率

1.30%

发文量

267

审稿时长

1 months

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