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Pathogenic Implications of the THY1/NF-κB Feedback Relationship in Osteoarthritis and Its Potential as a Therapeutic
Yiqun Yan1,2, Chen Wang1,2, Mingjun Zhang1,2
1Department of Orthopaedics, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230601, People's Republic of China.
Background:
Osteoarthritis (OA) is a chronic inflammatory disease primarily characterized by cartilage damage, and its pathological mechanisms remain to be elucidated.
Objective:
This study aimed to identify potential therapeutic targets for OA and to further explore their associated molecular mechanisms.
Methods:
Candidate OA-associated genes were identified by integrating differential expression analysis, WGCNA, and PPI network analysis. Diagnostic marker genes were subsequently determined using machine-learning algorithms (RF, LASSO, and SVM-RFE) and further validated by ROC analysis and nomogram modeling. Single-cell sequencing analyses were conducted to characterize the temporal dynamics of these marker genes across the developmental trajectory of OA chondrocytes. Both in vitro and in vivo experiments were performed to confirm the expression of key molecules and the activation of relevant pathways. In addition, berberine, a natural isoquinoline alkaloid with anti-inflammatory potential, was selected as a candidate compound to evaluate its interaction with THY1 by molecular docking and molecular dynamics simulation.
Results:
A total of 19 candidate OA-associated hub genes were identified. By integrating three machine-learning algorithms, THY1 was determined as a diagnostic marker gene for OA, and ROC curves and a nomogram model confirmed its favorable diagnostic/predictive performance. Single-cell sequencing further suggested a gradual upregulation of THY1 during chondrocyte development in OA. Both in vitro and in vivo experiments supported the feasibility of THY1 as a potential therapeutic target. Computational simulations demonstrated favorable binding between berberine and THY1.
Conclusion:
This study suggests that THY1 may serve as a diagnostic biomarker for OA and may be involved in disease progression through its association with the NF-κB signaling pathway. Moreover, our computational simulations provide preliminary and predictive structural insights into the potential interaction between berberine and THY1, thereby expanding possible research directions for berberine-based approaches in OA.
Insights
This study identifies THY1 as a promising diagnostic biomarker for osteoarthritis (OA). Computational analysis also suggests berberine may interact with THY1, offering potential new OA treatment avenues.
Area of Science:
- Biochemistry
- Genomics
- Computational Biology
Background:
- Osteoarthritis (OA) is a chronic inflammatory condition characterized by cartilage degradation.
- The precise pathological mechanisms underlying OA progression require further elucidation.
- Identifying novel therapeutic targets is crucial for effective OA management.
Purpose of the Study:
- To identify and validate diagnostic biomarkers for osteoarthritis.
- To explore potential molecular mechanisms involved in OA pathogenesis.
- To investigate THY1 as a therapeutic target and its interaction with berberine.
Main Methods:
- Integrated differential gene expression, WGCNA, and PPI network analyses to identify OA-associated genes.
- Employed machine learning (RF, LASSO, SVM-RFE) and ROC analysis for diagnostic marker selection.
- Utilized single-cell sequencing, in vitro/in vivo experiments, and molecular docking/dynamics simulations.
Main Results:
- Identified 19 candidate OA-associated hub genes, with THY1 selected as a key diagnostic marker.
- Validated THY1's diagnostic and predictive performance using ROC curves and nomogram modeling.
- Confirmed THY1 upregulation in OA chondrocytes and its potential as a therapeutic target, with favorable berberine binding predicted.
Conclusions:
- THY1 emerges as a potential diagnostic biomarker for osteoarthritis.
- THY1's role in OA progression, potentially via the NF-κB pathway, warrants further investigation.
- Computational findings suggest berberine as a potential therapeutic agent for OA by interacting with THY1.
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