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Potential involvement of the KLF2-GPX4 axis in ferroptosis during S.aureus-induced osteomyelitis
Jian Sun1,2, Xingbo Cai1, Junhui Qi1,2
1Department of Orthopedics, 920th Hospital of Joint Logistics Support Force, 212 Daguan Road, Xishan District, Kunming, 650032, People's Republic of China.
Background:
Increasing evidence suggests that ferroptosis plays a pivotal role in Staphylococcus aureus (S. aureus)-induced osteomyelitis. However, the regulatory mechanisms underlying ferroptosis-related genes (FRGs) in osteomyelitis remain poorly understood. This study aimed to identify key FRGs and elucidate their regulatory roles in osteomyelitis.
Methods:
Key FRGs were identified using least absolute shrinkage and selection operator (LASSO) logistic regression and support vector machine-recursive feature elimination (SVM-RFE) algorithms based on transcriptomic data from the Gene Expression Omnibus (GEO) database. Bone marrow mesenchymal stromal cells (BMSCs) were isolated, characterized, and infected with S. aureus protein A (SpA) to construct an in vitro model. Cell viability, osteogenic differentiation, inflammation, and gene expression were assessed using Cell Counting Kit-8 (CCK-8), Alizarin Red S staining, enzyme-linked immunosorbent assay (ELISA), and quantitative reverse transcription polymerase chain reaction (qRT-PCR). In vivo, a mouse model of S. aureus-induced osteomyelitis was established, and the role of KLF2 was examined by micro-computed tomography (micro-CT), ELISA, histological staining, immunohistochemistry, immunofluorescence, and qRT-PCR.
Results:
A total of 683 differentially expressed FRGs were identified. Ten candidate biomarkers were screened using LASSO and SVM-RFE, of which TXN, KLF2, HSPA8, CCT3, and AKR1C3 were consistently validated across training and validation datasets. These genes were associated with immune regulation, protein synthesis, and multiple ribosome- and metabolism-related pathways. In vitro, SpA treatment increased inflammation response, reduced BMSC proliferation and osteogenic differentiation, upregulated HSPA8, TXN, and CCT3, and downregulated KLF2 and its putative downstream target GPX4. In vivo, KLF2 overexpression alleviated S. aureus-induced bone loss, inflammation, and ferroptosis, while promoting angiogenesis and osteogenesis, in part through modulation of GPX4.
Conclusion:
This study highlights KLF2 as a potential protective factor in S. aureus-induced osteomyelitis, possibly by regulating GPX4 and ferroptosis.
Insights
This study identifies KLF2 as a key regulator in Staphylococcus aureus (S. aureus)-induced osteomyelitis. KLF2 overexpression protects against bone loss and inflammation by modulating ferroptosis, offering a potential therapeutic target.
Area of Science:
- Biomedical research
- Molecular biology
- Immunology
Background:
- Ferroptosis is increasingly recognized as crucial in Staphylococcus aureus (S. aureus)-induced osteomyelitis.
- Regulatory mechanisms of ferroptosis-related genes (FRGs) in osteomyelitis are not well understood.
Purpose of the Study:
- Identify key FRGs involved in osteomyelitis.
- Elucidate the regulatory roles of these genes, particularly KLF2, in the disease process.
Main Methods:
- Utilized LASSO and SVM-RFE algorithms on GEO transcriptomic data to identify key FRGs.
- Established in vitro (BMSC infection) and in vivo (mouse osteomyelitis model) systems.
- Assessed cell viability, osteogenic differentiation, inflammation, and gene expression using CCK-8, Alizarin Red S, ELISA, and qRT-PCR.
Main Results:
- Identified 683 differentially expressed FRGs, with TXN, KLF2, HSPA8, CCT3, and AKR1C3 validated as key biomarkers.
- In vitro, S. aureus protein A (SpA) upregulated inflammation and certain FRGs while downregulating KLF2 and GPX4.
- In vivo, KLF2 overexpression reduced bone loss, inflammation, and ferroptosis, promoting angiogenesis and osteogenesis via GPX4 modulation.
Conclusions:
- KLF2 acts as a protective factor in S. aureus-induced osteomyelitis.
- KLF2 may exert its protective effects by regulating GPX4 and ferroptosis.
- KLF2 represents a potential therapeutic target for osteomyelitis treatment.
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