Osteoclast Differentiation Is Suppressed by Increased &lt;i&gt;O&lt;/i&gt;-GlcNAcylation Due to Thiamet G Treatment

Takeuchi, Tomoharu; Horimoto, Yasuhiro; Oyama, Midori; Nakatani, Sachie; Kobata, Kenji; Tamura, Masahito; Arata, Yoichiro; Hatanaka, Tomomi

doi:10.1248/bpb.b20-00221

Cited by 9 publications

(12 citation statements)

References 19 publications

(29 reference statements)

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“…These studies also showed that O-GlcNAcylation occurs in a cell lineage-specific manner during cell differentiation. [12][13][14][15][16] The levels of glucose uptake and utilization are relatively high in pluripotent stem cells, and their levels change as the cells begin to differentiate. 15 Changes in glucose uptake and utilization levels also result in various global O-GlcNAc levels during differentiation.…”

Section: Introductionmentioning

confidence: 99%

O‐GlcNAcylation drives calcium signaling toward osteoblast differentiation: A bioinformatics‐oriented study

et al. 2021

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This study aimed to reveal the possible mechanisms by which O-linked-Nacetylglucosaminylation (O-GlcNAcylation) regulates osteoblast differentiation using a series of bioinformatics-oriented experiments. To examine the influence of O-GlcNAcylation levels on osteoblast differentiation, osteoblastic MC3T3-E1 cells were treated with O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) inhibitors. Correlations between the levels of O-GlcNAcylation and the expression of osteogenic markers as well as OGT were evaluated by qPCR and western blotting.The O-GlcNAcylated proteins assumed to correlate with Runx2 expression were retrieved from several public databases and used for further bioinformatics analysis. Following the findings of the bioinformatics analysis, intracellular calcium ([Ca 2+ ] i ) was monitored in the cells treated with OGT and OGA inhibitors using a confocal laser-scanning microscope (CLS). The interaction effect between O-GlcNAcylation and [Ca 2+ ] i on osteogenic marker expression was determined using stable OGT knockdown MC3T3-E1 cells. O-GlcNAcylation was positively associated with osteoblast differentiation. The time-course profile of global O-GlcNAcylated proteins showed a distinctive pattern with different molecular weights during osteoblast differentiation. The expression pattern of several O-GlcNAcylated proteins was significantly similar to that of Runx2 expression. Bioinformatic analysis of the retrieved Runx2-related-O-GlcNAcylated-proteins revealed the importance of [Ca 2+ ] i . CLS showed that alteration of O-GlcNAcylation rapidly changed [Ca 2+ ] i in MC3T3-E1 cells. O-GlcNAcylation and [Ca 2+ ] i showed an interaction effect on the expression of osteogenic markers. OGT knockdown disrupted the [Ca 2+ ] i -induced expression changes of osteogenic markers. O-GlcNAcylation interacts with [Ca 2+ ] i and elicits osteoblast differentiation by regulating the expression of osteogenic markers.

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Section: Introductionmentioning

confidence: 99%

O‐GlcNAcylation drives calcium signaling toward osteoblast differentiation: A bioinformatics‐oriented study

et al. 2021

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“…Studies have shown that OSMI-1 can promote tumor cell apoptosis and has certain prospects for cancer treatment [ 39 , 40 ]. It has been shown to be negatively regulated in osteoclasts [ 41 ] and positively regulated during embryonic differentiation [ 42 ] and in corneal epithelial cells [ 43 ]. In this study, using in vitro experiments, we proved that the application of OSMI-1 to inhibit the function of OGT can improve the degree of damage to lung epithelial cells caused by hyperoxia, enhance cell metabolism and proliferation, decrease apoptosis, and promote cell cycle rates.…”

Section: Discussionmentioning

confidence: 99%

O-linked N-acetylglucosamine affects mitochondrial homeostasis by regulating Parkin-dependent mitophagy in hyperoxia-injured alveolar type II cells injury

Liu

et al. 2023

Respir Res

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Background The level of linked N-acetylglucosamine (O-GlcNAc) has been proved to be a sensor of cell state, but its relationship with hyperoxia-induced alveolar type 2 epithelial cells injure and bronchopulmonary dysplasia (BPD) has not been clarified. In this study, we evaluated if these effects ultimately led to functional damage in hyperoxia-induced alveolar cells. Methods We treated RLE-6TN cells at 85% hyperoxia for 0, 24 and 48 h with Thiamet G (TG), an OGA inhibitor; OSMI-1 (OS), an OGT inhibitor; or with UDP-GlcNAc, which is involved in synthesis of O-GlcNAc as a donor. The metabolic rerouting, cell viability and apoptosis resulting from the changes in O-GlcNAc glycosyltransferase levels were evaluated in RLE-6TN cells after hyperoxia exposure. We constructed rat Park2 overexpression and knockdown plasmmids for in vitro verification and Co-immunoprecipitation corroborated the binding of Parkin and O-GlcNAc. Finally, we assessed morphological detection in neonatal BPD rats with TG and OS treatment. Results We found a decrease in O-GlcNAc content and levels of its metabolic enzymes in RLE-6TN cells under hyperoxia. However, the inhibition of OGT function with OSMI-1 ameliorated hyperoxia-induced lung epithelial cell injury, enhanced cell metabolism and viability, reduced apoptosis, and accelerated the cell proliferation. Mitochondrial homeostasis was affected by O-GlcNAc and regulated Parkin. Conclusion The results revealed that the decreased O-GlcNAc levels and increased O-GlcNAcylation of Parkin might cause hyperoxia-induced alveolar type II cells injurys.

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“…Our findings on the role of O-GlcNAcylation in osteoclasts contradict a few previous reports. For example, increased O-GlcNAcylation by an Oga inhibitor, O-(2-acetamido-2deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate (PUGNAc), or a glucosamine treatment in Raw264.7 cells inhibits osteoclast differentiation and activity [48][49][50]. This discrepancy could be due to the different cellular contexts and the off-target effects of the different treatments; however, this ironical observation reminds us of the "optimal zone" of O-GlcNAcylation [10].…”

Section: Discussionmentioning

confidence: 99%

Hexosamine Biosynthetic Pathway-Derived O-GlcNAcylation Is Critical for RANKL-Mediated Osteoclast Differentiation

Kim

Lee

et al. 2021

IJMS

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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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Osteoclast Differentiation Is Suppressed by Increased <i>O</i>-GlcNAcylation Due to Thiamet G Treatment

Cited by 9 publications

References 19 publications

O‐GlcNAcylation drives calcium signaling toward osteoblast differentiation: A bioinformatics‐oriented study

O‐GlcNAcylation drives calcium signaling toward osteoblast differentiation: A bioinformatics‐oriented study

O-linked N-acetylglucosamine affects mitochondrial homeostasis by regulating Parkin-dependent mitophagy in hyperoxia-injured alveolar type II cells injury

Hexosamine Biosynthetic Pathway-Derived O-GlcNAcylation Is Critical for RANKL-Mediated Osteoclast Differentiation

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