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Selenium-sensitive histone deacetylase 2 is required for forkhead box O3A and regulates extracellular matrix metabolism in cartilage

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A Correction to this article was published on 02 January 2023

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Abstract

Introduction

Selenium (Se) as well as selenoproteins are vital for osteochondral system development. Se deficiency (SeD) has a definite impact on the expression and activity of histone deacetylases (HDACs). Abnormal expression of some HDACs affects cartilage development. This current study aims to explore the relationship between differentially expressed HDACs and cartilage development, especially extracellular matrix (ECM) homeostasis maintenance, under SeD conditions.

Materials and methods

Dark Agouti rats and C28/I2 cell line under SeD states were used to detect the differently expressed HDAC by RT-qPCR, western blotting and IHC staining. Meanwhile, the biological roles of the above HDAC in cartilage development and homeostasis maintenance were confirmed by siRNA transfection, western blotting, RNA sequence and inhibitor treatment experiments.

Results

HDAC2 exhibited lower expression at protein level in both animals and chondrocytes during SeD condition. The results of cell-level experiments indicated that forkhead box O3A (FOXO3A), which was required to maintain metabolic homeostasis of cartilage matrix, was reduced by HDAC2 knockdown. Meanwhile, induced HDAC2 was positively associated with FOXO3A in rat SeD model. Meanwhile, knockdown of HDAC2 and FOXO3A led to an increase of intracellular ROS level, which activated NF-κB pathway. Se supplementary significantly inhibited the activation of NF-κB pathway with IL-1β treatment.

Conclusion

Our results suggested that low expression of HDAC2 under SeD condition increased ROS content by decreasing FOXO3A in chondrocytes, which led to the activation of NF-κB pathway and ECM homeostasis imbalance.

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Acknowledgements

The inbred Dark Agouti (DA) rats were provided by Prof. Rikard Holmdahl, Karolinska Institute, Sweden. The C28/I2 cell line is provided by Professor Junling Cao, from Institute of endemic diseases, Xi’an Jiaotong University Health Science Center.

Funding

This work was supported by National Natural Science Foundation of China (Project No. 82072432, 81970029).

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Xi’an Jiaotong University School of Basic Medical Sciences, West Yanta Street No.76, Xi’an, 710061, Shaanxi, People’s Republic of China

    Yitong Zhao, Yuanxu Guo, Mengyao Sun, Safdar Hussion, Huang Huang, Xinyu Huo, Fujun Zhang, Yan Han, Qilan Ning & Shemin Lu

  2. Department of Digestive Disease and Gastrointestinal Motility Research Room, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 Xi Wu Road, Xi’an, 710004, Shaanxi, People’s Republic of China

    Ying Zheng

  3. Department of Software Engineering, Xinjiang University School of Software, Urumqi, 830000, Xinjiang, People’s Republic of China

    Yutong Zhao

  4. Department of Joint Surgery, Xi’an Honghui Hospital, Easter Youyi Road No. 555, Xi’an, 710054, Shaanxi, People’s Republic of China

    Peng Xu

  5. Key Laboratory of Trace Elements and Endemic Diseases, Xi’an Jiaotong University School of Public Health, West Yanta Street No.76, Xi’an, 710061, Shaanxi, People’s Republic of China

    Jian Sun

Authors
  1. Yitong Zhao
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  2. Yuanxu Guo
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  3. Mengyao Sun
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  6. Huang Huang
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  8. Yutong Zhao
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  9. Fujun Zhang
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  10. Yan Han
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  11. Qilan Ning
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  12. Peng Xu
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  13. Jian Sun
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  14. Shemin Lu
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Contributions

SL and JS conceived, designed and supervised the study. YZ performed most of the experiments, analyzed and interpreted the data and wrote the original manuscript. YG, MS, YZ, SH, HH, XH, YZ, FZ, YH, QN. and PX. helped the experiments. JS. and SL obtained the funding and critically revised the article for important intellectual content, and take responsibility for the integrity of the work as a whole.

Corresponding authors

Correspondence to Jian Sun or Shemin Lu.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The experiments were approved by Institutional Animal Ethics Committee of the University (Permission ID: XJ2006Y039; Xi'an Jiaotong University, Xi'an, China) and were in compliance with ARRIVE guidelines and European Community specifications regarding the use of laboratory animals.

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Zhao, Y., Guo, Y., Sun, M. et al. Selenium-sensitive histone deacetylase 2 is required for forkhead box O3A and regulates extracellular matrix metabolism in cartilage. J Bone Miner Metab 40, 914–926 (2022). https://doi.org/10.1007/s00774-022-01369-9

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  • DOI: https://doi.org/10.1007/s00774-022-01369-9

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