Hexosamine Biosynthetic Pathway-Derived O-GlcNAcylation Is Critical for RANKL-Mediated Osteoclast Differentiation.
Hexosamine Biosynthetic Pathway-Derived O-GlcNAcylation Is Critical for RANKL-Mediated Osteoclast Differentiation.
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DOI：
10.3390/ijms22168888
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发表时间：
2021-08-18
影响因子：
5.6
通讯作者：
You JS
中科院分区：
文献类型：
--
作者：
Kim MJ;Kim HS;Lee S;Min KY;Choi WS;You JS
通过O-GlcNAc转移酶（OGT）进行的O-连接-N-乙酰葡糖胺化（O-GlcNAc化）是通过己糖胺生物合成途径（HBP）进行的营养响应性翻译后修饰（PTM）。各种转录因子（TF）被O-GlcNAc酰化，影响其活性并显著促进从存活到细胞分化的细胞过程。鉴于O-GlcNAc修饰的多效性功能，已在各个领域进行了研究;然而，O-GlcNAc修饰在破骨细胞分化过程中的作用仍有待探索。在核因子-κ B受体激活剂（NF-κB）配体（RANKL）介导的破骨细胞分化过程中的动力学转录组分析显示，主要营养代谢的关系，HBP对该过程至关重要。我们观察到与HBP活化相关的关键基因，包括Nagk，Gfpt 1和Ogt，在破骨细胞分化过程中上调，而整体O-GlcNAc化伴随增加。通过小分子抑制剂OSMI-1抑制O-GlcNAc化，通过控制其PTM O-GlcNAc化，破坏NF-κB p65和活化T细胞核因子c1（NFATc 1）向细胞核的移位，从而减少体外和体内破骨细胞分化。此外，OSMI-1与骨靶向治疗对破骨细胞生成具有协同作用。最后，用shRNA敲低Ogt（shOgt）模拟OSMI-1对破骨细胞生成的作用。在破骨细胞分化过程中靶向O-GlcNAc化可能是破骨细胞激活的骨疾病的一种有价值的治疗方法。
O-linked-N-acetylglucosaminylation (O-GlcNAcylation) performed by O-GlcNAc transferase (OGT) is a nutrient-responsive post-translational modification (PTM) via the hexosamine biosynthetic pathway (HBP). Various transcription factors (TFs) are O-GlcNAcylated, affecting their activities and significantly contributing to cellular processes ranging from survival to cellular differentiation. Given the pleiotropic functions of O-GlcNAc modification, it has been studied in various fields; however, the role of O-GlcNAcylation during osteoclast differentiation remains to be explored. Kinetic transcriptome analysis during receptor activator of nuclear factor-kappaB (NF-κB) ligand (RANKL)-mediated osteoclast differentiation revealed that the nexus of major nutrient metabolism, HBP was critical for this process. We observed that the critical genes related to HBP activation, including Nagk, Gfpt1, and Ogt, were upregulated, while the global O-GlcNAcylation was increased concomitantly during osteoclast differentiation. The O-GlcNAcylation inhibition by the small-molecule inhibitor OSMI-1 reduced osteoclast differentiation in vitro and in vivo by disrupting the translocation of NF-κB p65 and nuclear factor of activated T cells c1 (NFATc1) into the nucleus by controlling their PTM O-GlcNAcylation. Furthermore, OSMI-1 had a synergistic effect with bone target therapy on osteoclastogenesis. Lastly, knocking down Ogt with shRNA (shOgt) mimicked OSMI-1’s effect on osteoclastogenesis. Targeting O-GlcNAcylation during osteoclast differentiation may be a valuable therapeutic approach for osteoclast-activated bone diseases.
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