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Ortho-silicic Acid Prevents Glucocorticoid-Induced Femoral Head Necrosis by Promoting Akt Phosphorylation to Inhibit Endoplasmic Reticulum Stress-Mediated Apoptosis and Enhance Angiogenesis and Osteogenesis

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Abstract

Glucocorticoid-induced osteonecrosis of the femoral head (SONFH) is the most prevalent form of secondary osteonecrosis affecting the femoral head. Glucocorticoids can cause damage to both vascular endothelial cells and osteoblasts. Previous studies have demonstrated that silicon can improve the resistance of vascular endothelial cells to oxidative stress and positively impact bone health. However, the impact of silicon on SONFH has yet to be investigated. We examined the influence of ortho-silicic acid (OSA, Si(OH)4) on the apoptosis and proliferation of vascular endothelial cells after glucocorticoid induction. Additionally, we evaluated the expression of apoptosis-related genes such as cleaved-caspase-3, Bcl-2 and Bax. The impact of glucocorticoids and OSA on the function of vascular endothelial cells was evaluated through wound healing, transwell and angiogenesis assays. Osteogenic function was subsequently evaluated through alizarin red staining, alkaline phosphatase staining and expression levels of osteogenic genes like RUNX2 and ALP. Moreover, we investigated the potential role of OSA in vivo using the SONFH animal model. At concentrations below 100 μM, OSA exhibits no toxicity on vascular endothelial cells and effectively reverses glucocorticoid-induced apoptosis in these cells. OSA increases the resilience of vascular endothelial cells against oxidative stress and enhances osteoblast differentiation. Our study revealed that glucocorticoids activate endoplasmic reticulum stress, a process that mediates the apoptosis of vascular endothelial cells. OSA ameliorated the endoplasmic reticulum stress associated with glucocorticoids through the increased expression of p-Akt levels. In vivo, OSA treatment effectively improved SONFH by enhancing vascular endothelial cell function and promoting osteogenic differentiation. OSA counteracted the adverse effects of glucocorticoids both in vitro and in vivo, demonstrating a beneficial therapeutic effect on SONFH.

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Data Availability

All data generated and analysed during this study are included in this published article and supplementary information file.

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Acknowledgements

We thank the Translational Medicine Core Facility of Shandong University, Laboratory of Basic Medical Sciences of Qilu Hospital of Shandong University, School of Basic Medical Sciences, Shandong University, for consultation and instrument availability that supported this work.

Funding

This work was supported by the Natural Science Foundation of Shandong Province (ZR2020QH080).

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Author notes

  1. Guangjun Jiao and Yunzhen Chen contributed equally to this work and shared corresponding authorship.

Authors and Affiliations

  1. Department of Orthopaedics, Qilu Hospital of Shandong University, Wenhuaxi Road 107, Jinan, Shandong, 250012, People’s Republic of China

    Zhenqian Sun, Jian Wang, Zhongjie Ji, Jinlong Ma, Yunzhen Chen & Guangjun Jiao

  2. Shandong University, Wenhuaxi Road 107, Jinan, Shandong Province, People’s Republic of China

    Zhenqian Sun, Jian Wang, Zhongjie Ji & Jinlong Ma

Authors
  1. Zhenqian Sun
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Contributions

ZS contributed to the conceptualisation, methodology and original draft writing. JW and ZJ carried out the data analysis and review, editing and writing of the manuscript. ZS and JW participated in the formal analysis and software. JM contributed to the visualisation and investigation. ZJ contributed to the resources and validation. YC contributed to the supervision. GJ was responsible for the project administration and funding acquisition. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yunzhen Chen or Guangjun Jiao.

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Ethics Approval and Consent to Participate

This study was approved by the Medical Ethics Committee of Qilu Hospital of Shandong University. All animal studies complied with the principles based on the International Guiding Principles for Biomedical Research Involving Animals.

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Informed consent was obtained from all subjects involved in the study.

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The authors declare no competing interests.

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Sun, Z., Wang, J., Ji, Z. et al. Ortho-silicic Acid Prevents Glucocorticoid-Induced Femoral Head Necrosis by Promoting Akt Phosphorylation to Inhibit Endoplasmic Reticulum Stress-Mediated Apoptosis and Enhance Angiogenesis and Osteogenesis. Biol Trace Elem Res (2024). https://doi.org/10.1007/s12011-023-04048-6

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