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Effects of selenium-mediated RUNX2 overexpression and its transcriptome alterations on Chondrocyte injury in Kashin
Di Zhang1,2, Qiang Li2, Xiaoli Yang3
1National and Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Objective:
Kashin-Beck disease (KBD) is a nutrition-related osteoarthropathy characterized by excessive apoptosis and matrix destruction. Micronutrient selenium (Se) deficiency is recognized as a major environmental risk factor. This study aimed to investigate the role of RUNX2 in cartilage injury associated with KBD.
Methods:
RUNX2 expression in articular cartilage from KBD patients was assessed by immunohistochemistry. RUNX2 mRNA expression and promoter methylation were analyzed using qRT-PCR and qMSP. A chondrocyte injury model was established under Se-deficient conditions, while a RUNX2 overexpression model was generated by lentiviral transfection and further analyzed by RNA sequencing.
Results:
The proportion of RUNX2-positive cells in KBD cartilage was significantly higher than in controls. RUNX2 mRNA levels were elevated, whereas methylation levels were reduced in KBD samples. Inhibition of DNA methylation confirmed that decreased methylation of RUNX2 promoted its transcription. In Se-deficient chondrocytes, decreased RUNX2 methylation, increased RUNX2 expression, and higher rates of apoptosis and necrosis were observed, all of which were reversed by Se supplementation. Moreover, RUNX2 overexpression further increased chondrocyte apoptosis and necrosis. Transcriptomic analysis revealed 263 upregulated and 216 downregulated genes, predominantly enriched in the TNF and MAPK signaling pathways.
Conclusion:
Micronutrient Se deficiency may contribute to the pathogenesis of KBD by modulating RUNX2 expression and inducing excessive chondrocyte apoptosis, while Se supplementation exerts a protective effect. RUNX2 plays a critical role in KBD progression and may represent a potential therapeutic target.
Insights
Selenium deficiency contributes to Kashin-Beck disease (KBD) by increasing RUNX2 expression and chondrocyte apoptosis. Selenium supplementation protects against KBD, highlighting RUNX2 as a therapeutic target.
Area of Science:
- Biochemistry
- Molecular Biology
- Pathology
Background:
- Kashin-Beck disease (KBD) is a nutrition-related osteoarthropathy linked to selenium (Se) deficiency.
- KBD involves excessive chondrocyte apoptosis and matrix destruction in articular cartilage.
Purpose of the Study:
- Investigate the role of RUNX2 in KBD-associated cartilage injury.
- Determine the impact of selenium deficiency on RUNX2 expression and chondrocyte function.
Main Methods:
- Immunohistochemistry and qRT-PCR to assess RUNX2 expression in KBD cartilage.
- Analysis of RUNX2 promoter methylation (qMSP) in patient samples.
- In vitro models of Se-deficient chondrocytes and RUNX2 overexpression, followed by RNA sequencing.
Main Results:
- Elevated RUNX2 expression and reduced promoter methylation in KBD cartilage.
- Se deficiency increased chondrocyte apoptosis and necrosis, associated with decreased RUNX2 methylation and increased RUNX2 expression.
- Se supplementation reversed these effects; RUNX2 overexpression exacerbated apoptosis.
Conclusions:
- Selenium deficiency promotes KBD pathogenesis by modulating RUNX2, leading to chondrocyte apoptosis.
- RUNX2 is a critical factor in KBD progression and a potential therapeutic target.
- Selenium supplementation offers a protective effect against KBD.
