Glucocorticoid-induced activation of NOX/ROS/NF-κB signaling in MSCs contributes to the development of GONFH

  • Apoptosis. 2023 Jun 12. doi: 10.1007/s10495-023-01860-2.
Huihui Xu  1  2  3 ,  Qinghe Zeng  1  2  3 ,  Kaiao Zou  1  2  3 ,  Haipeng Huang  1  2  3 ,  Jiali Chen  1  3 ,  Pinger Wang  1  3 ,  Wenhua Yuan  1  3 ,  Luwei Xiao  1  3 ,  Peijian Tong  1  2  3 ,  Hongting Jin  4  5  6
Affiliations
  • 1. The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, 310006, China.
  • 2. The First College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
  • 3. Institute of Orthopaedics and Traumatology of Zhejiang Province, Hangzhou, Zhejiang, 310053, China.
  • 4. The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, 310006, China. [email protected].
  • 5. The First College of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China. [email protected].
  • 6. Institute of Orthopaedics and Traumatology of Zhejiang Province, Hangzhou, Zhejiang, 310053, China. [email protected].
PMID: 37306805 DOI: 10.1007/s10495-023-01860-2
Abstract

Background: This study aimed to investigate the pathogenic factors of glucocorticoids (GCs)-induced osteonecrosis of the femoral head (GONFH) and its underlying pathogenesis in vivo and in vitro.

Methods: Radiographical (µCT) scanning, histopathological, immunohistochemical, Reactive Oxygen Species (ROS) and tunel staining were conducted on GONFH patients and rats. ROS, tunel, flow cytometry, Alkaline Phosphatase, Oil red O staining, reverse transcription‑quantitative PCR and western blotting were applied to elucidate the exact pathogenesis mechanism.

Results: Clinical and animal studies demonstrated increased levels of ROS, aggravated oxidative stress (OS) microenvironment, augmented Apoptosis and imbalance in osteogenic/lipogenic in the GONFH group compared to the control group. The fate of mesenchymal stem cells (MSCs) directed by GCs is a crucial factor in determining GONFH. In vitro studies further revealed that GCs promote excessive ROS production through the expression of NOX family proteins, leading to a deterioration of the OS microenvironment in MSCs, ultimately resulting in Apoptosis and imbalance in osteogenic/lipogenic differentiation. Furthermore, our results confirmed that the NOX inhibitor-diphenyleneiodonium chloride and the NF-κB inhibitor-BAY 11-7082 ameliorated Apoptosis and osteogenic/lipogenic differentiation imbalance of MSCs induced by an excess of GCs.

Conclusion: We demonstrated for the first time that the aggravation of the OS microenvironment in MSCs caused by high doses of GCs leading to Apoptosis and differentiation imbalance is a crucial factor in the pathogenesis of GONFH, mediated through activating the NOX/ROS/NF-κB signaling pathway.

Keywords
Apoptosis; Differentiation; GONFH; Mesenchymal stem cell; Oxidative stress.
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