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Antioxidants
Special Issues
Role of Nrf2 and ROS in Bone Metabolism
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Role of Nrf2 and ROS in Bone Metabolism

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "ROS, RNS and RSS".

Deadline for manuscript submissions: closed (10 December 2024) | Viewed by 4275

Special Issue Editor

Dr. Hiroyuki Kanzaki

E-Mail Website
Guest Editor
Department of Orthodontics, School of Dental Medicine, Tsurumi University, Yokohama 230-8501, Japan
Interests: bone metabolism; reactive oxygen species (ROS); Nrf2; bone biology

Special Issue Information

Dear Colleagues,

Bone metabolism is regulated by the balance between bone formation and resorption. In recent years, it has become evident that oxidative stress, including the activities of reactive oxygen species (ROS), plays a crucial role in the regulation of  bone metabolism. For example, osteoclasts utilize intracellular ROS signaling after RANKL. 

In addition, Nrf2 (nuclear factor erythroid 2-related factor 2) is a key transcription factor that regulates the expression of antioxidant proteins and plays a crucial role in maintaining cellular redox homeostasis. Recent studies have shown that Nrf2 is involved in the regulation of bone metabolism via the modulation of the differentiation and function of osteoblasts and osteoclasts.

Moreover, the interplay between ROS and Nrf2 signaling pathways has been implicated in various bone disorders such as osteoporosis, osteoarthritis, periodontitis, and the healing of bone fractures. Understanding the molecular mechanisms that underlie the regulation of bone metabolism by ROS and Nrf2 could provide new insights into the pathogenesis of these bone disorders and lead to the development of novel therapeutic strategies.

This Special Issue aims to gather original research articles, reviews, and short communications that explore the role of Nrf2 and ROS in bone metabolism. Topics of interest include, but are not limited to, the following:

  • Molecular mechanisms of Nrf2 and ROS signaling in osteoblast and osteoclast differentiation and function;
  • Nrf2 and ROS in bone disorders such as osteoporosis, osteoarthritis, periodontitis, and bone fracture healing;
  • Crosstalk between Nrf2 and other signaling pathways in bone metabolism;
  • Antioxidant therapies targeting Nrf2 and ROS for the treatment of bone disorders;
  • Novel experimental models and techniques to study the role of Nrf2 and ROS in bone metabolism.

We invite researchers from various fields, including bone biology, redox biology, and molecular biology, to contribute to this Special Issue and share their latest findings and perspectives on the role of Nrf2 and ROS in bone metabolism.

Dr. Hiroyuki Kanzaki
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • bone metabolism
  • reactive oxygen species (ROS)
  • oxidative stress
  • osteoblast
  • osteoclast
  • inflammation
  • Nrf2
  • Keap1
  • Bach1
  • FOXOs
  • sirtuins
  • anti-oxidation
  • osteoporosis
  • osteoarthritis
  • bone fracture healing

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Published Papers (3 papers)

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16 pages, 3897 KiB  
Article
Divergent Requirements for Glutathione Biosynthesis During Osteoclast Differentiation In Vitro and In Vivo
by Guoli Hu, Amy L. Whitaker, Guo-Fang Zhang and Courtney M. Karner
Antioxidants 2025, 14(2), 197; https://doi.org/10.3390/antiox14020197 - 10 Feb 2025
Viewed by 838
Abstract
Glutathione (GSH) is the most abundant antioxidant in the cell, and it is responsible for neutralizing reactive oxygen species (ROS). ROS can promote osteoclast differentiation and stimulate bone resorption and are some of the primary drivers of bone loss with aging and loss [...] Read more.
Glutathione (GSH) is the most abundant antioxidant in the cell, and it is responsible for neutralizing reactive oxygen species (ROS). ROS can promote osteoclast differentiation and stimulate bone resorption and are some of the primary drivers of bone loss with aging and loss of sex steroids. Despite this, the role of GSH biosynthesis during osteoclastogenesis remains controversial. Here, we show that the requirements for GSH biosynthesis during osteoclastogenesis in vitro and in vivo are unique. Using a metabolomics approach, we discovered that both oxidative stress and GSH biosynthesis increase during osteoclastogenesis. Inhibiting GSH biosynthesis in vitro via the pharmacological or genetic inhibition of glutamate cysteine ligase (GCLC) prevented osteoclast differentiation. Conversely, the genetic ablation of GCLC in myeloid cells using LysMCre resulted in a decrease in bone mass in both male and female mice. The decreased bone mass of the LysMCre;Gclcfl/fl mice was attributed to increased osteoclast numbers and elevated bone resorption. Collectively, our data provide strong genetic evidence that GSH biosynthesis is essential for the regulation of osteoclast differentiation and bone resorption in mice. Moreover, these findings highlight the necessity of complementing in vitro studies with in vivo genetic studies. Full article
(This article belongs to the Special Issue Role of Nrf2 and ROS in Bone Metabolism)
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Figure 1

24 pages, 17809 KiB  
Article
Transcriptomic Characterization Reveals Mitochondrial Involvement in Nrf2/Keap1-Mediated Osteoclastogenesis
by Eiko Sakai and Takayuki Tsukuba
Antioxidants 2024, 13(12), 1575; https://doi.org/10.3390/antiox13121575 - 20 Dec 2024
Cited by 1 | Viewed by 825
Abstract
Although osteoclasts play crucial roles in the skeletal system, the mechanisms that underlie oxidative stress during osteoclastogenesis remain unclear. The transcription factor Nrf2 and its suppressor, Keap1, function as central mediators of oxidative stress. To further elucidate the function of Nrf2/Keap1-mediated oxidative stress [...] Read more.
Although osteoclasts play crucial roles in the skeletal system, the mechanisms that underlie oxidative stress during osteoclastogenesis remain unclear. The transcription factor Nrf2 and its suppressor, Keap1, function as central mediators of oxidative stress. To further elucidate the function of Nrf2/Keap1-mediated oxidative stress regulation in osteoclastogenesis, DNA microarray analysis was conducted in this study using wild-type (WT), Keap1 knockout (Keap1 KO), and Nrf2 knockout (Nrf2 KO) osteoclasts. Principal component analysis showed that 403 genes, including Nqo1, Il1f9, and Mmp12, were upregulated in Keap1 KO compared with WT osteoclasts, whereas 24 genes, including Snhg6, Ccdc109b, and Wfdc17, were upregulated in Nrf2 KO compared with WT osteoclasts. Moreover, 683 genes, including Car2, Calcr, and Pate4, were upregulated in Nrf2 KO cells compared to Keap1 KO cells. Functional analysis by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis showed upregulated genes in Nrf2 KO osteoclasts were mostly enriched in oxidative phosphorylation. Furthermore, GeneMANIA predicted the protein–protein interaction network of novel molecules such as Rufy4 from genes upregulated in Nrf2 KO osteoclasts. Understanding the complex interactions between these molecules may pave the way for developing promising therapeutic strategies against bone metabolic diseases caused by increased osteoclast differentiation under oxidative stress. Full article
(This article belongs to the Special Issue Role of Nrf2 and ROS in Bone Metabolism)
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Figure 1

16 pages, 10571 KiB  
Article
Activation of Nuclear Factor Erythroid 2-Related Factor 2 Transcriptionally Upregulates Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 Expression and Inhibits Ectopic Calcification in Mice
by Ida Tomomi, Hiroyuki Kanzaki, Miho Shimoyama, Syunnosuke Tohyama, Misao Ishikawa, Yuta Katsumata, Chihiro Arai, Satoshi Wada, Shugo Manase and Hiroshi Tomonari
Antioxidants 2024, 13(8), 896; https://doi.org/10.3390/antiox13080896 - 24 Jul 2024
Cited by 1 | Viewed by 1715
Abstract
Calcification plays a key role in biological processes, and breakdown of the regulatory mechanism results in a pathological state such as ectopic calcification. We hypothesized that ENPP1, the enzyme that produces the calcification inhibitor pyrophosphate, is transcriptionally regulated by Nrf2, and that Nrf2 [...] Read more.
Calcification plays a key role in biological processes, and breakdown of the regulatory mechanism results in a pathological state such as ectopic calcification. We hypothesized that ENPP1, the enzyme that produces the calcification inhibitor pyrophosphate, is transcriptionally regulated by Nrf2, and that Nrf2 activation augments ENPP1 expression to inhibit ectopic calcification. Cell culture experiments were performed using mouse osteoblastic cell line MC3T3-E1. Nrf2 was activated by 5-aminolevulinic acid and sodium ferrous citrate. Nrf2 overexpression was induced by the transient transfection of an Nrf2 expression plasmid. ENPP1 expression was monitored by real-time RT-PCR. Because the promoter region of ENPP1 contains several Nrf2-binding sites, chromatin immunoprecipitation using an anti-Nrf2 antibody followed by real-time PCR (ChIP-qPCR) was performed. The relationship between Nrf2 activation and osteoblastic differentiation was examined by alkaline phosphatase (ALP) and Alizarin red staining. We used mice with a hypomorphic mutation in ENPP1 (ttw mice) to analyze whether Nrf2 activation inhibits ectopic calcification. Nrf2 and Nrf2 overexpression augmented ENPP1 expression and inhibited osteoblastic differentiation, as indicated by ALP expression and calcium deposits. ChIP-qPCR showed that some putative Nrf2-binding sites in the ENPP1 promoter region were bound by Nrf2. Nrf2 activation inhibited ectopic calcification in mice. ENPP1 gene expression was transcriptionally regulated by Nrf2, and Nrf2 activation augmented ENPP1 expression, leading to the attenuation of osteoblastic differentiation and ectopic calcification in vitro and in vivo. Nrf2 activation has a therapeutic potential for preventing ectopic calcification. Full article
(This article belongs to the Special Issue Role of Nrf2 and ROS in Bone Metabolism)
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