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Transcriptomic Characterization Reveals Mitochondrial Involvement in Nrf2/Keap1-Mediated Osteoclastogenesis.

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  • 1Department of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, 1-7-1, Sakamoto, Nagasaki 852-8588, Japan.

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|January 8, 2025
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Summary

Investigating oxidative stress in osteoclastogenesis, this study reveals gene expression changes in Keap1 and Nrf2 knockout models. Findings highlight potential therapeutic targets for bone metabolic diseases.

Keywords:
GeneMANIAKeap1Nrf2gene ontologyosteoclastoxidative stresstranscriptome

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Osteoclasts are vital for skeletal health, but the role of oxidative stress in their formation (osteoclastogenesis) is not fully understood.
  • The Nrf2-Keap1 pathway is a key regulator of cellular responses to oxidative stress.

Purpose of the Study:

  • To investigate the function of Nrf2/Keap1-mediated oxidative stress regulation in osteoclastogenesis.
  • To identify genes and pathways affected by Nrf2 and Keap1 deficiency during osteoclast differentiation.

Main Methods:

  • DNA microarray analysis was performed on wild-type (WT), Keap1 knockout (Keap1 KO), and Nrf2 knockout (Nrf2 KO) osteoclasts.
  • Gene expression profiles were analyzed using Principal Component Analysis (PCA).
  • Functional enrichment analyses (Gene Ontology, KEGG) and protein-protein interaction network prediction (GeneMANIA) were conducted.

Main Results:

  • Compared to WT, Keap1 KO osteoclasts showed upregulation of 403 genes (e.g., Nqo1, Il1f9, Mmp12).
  • Nrf2 KO osteoclasts showed upregulation of 24 genes (e.g., Snhg6, Ccdc109b, Wfdc17) compared to WT.
  • A significant number of genes (683) were upregulated in Nrf2 KO versus Keap1 KO osteoclasts, with enrichment in oxidative phosphorylation pathways.
  • GeneMANIA identified novel interactions, including Rufy4, among upregulated genes in Nrf2 KO osteoclasts.

Conclusions:

  • The Nrf2-Keap1 pathway significantly influences gene expression during osteoclastogenesis.
  • Upregulated genes in Nrf2 KO osteoclasts are linked to oxidative phosphorylation, suggesting a role in metabolic regulation.
  • Understanding these molecular interactions may lead to new therapeutic strategies for bone diseases associated with aberrant osteoclast activity and oxidative stress.