Deng Muhai, Tang Cong, Yin Li, Yang Junjun, Chen Zhiyu, Jiang Yunsheng, Huang Yang, Chen Cheng
College of Medical Informatics, Chongqing Medical University, Chongqing, 400016, China.
Department of Orthopaedics, General Hospital of Western Theater Command, Chengdu, 610083, China.
Heliyon. 2024 Jul 31;10(15):e35263. doi: 10.1016/j.heliyon.2024.e35263. eCollection 2024 Aug 15.
Osteoarthritis (OA) is the most common form of joint diseases, with hallmark of cartilage degeneration. Recent studies have shown that the pathogenesis of OA is associated with chondrocyte necroptosis.
In this study, we used single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data to analyze necroptosis regulation in OA chondrocytes. We performed enrichment analysis, carried out experimental validation, constructed machine learning models, and docked drug molecules.
After least absolute shrinkage and selection operator (LASSO) algorithm screening, 4 hub genes (RIPK3, CYBB, HSP90AB1, and TRAF5) with diagnostic characteristics were obtained. Following the comparison of multiple models, the Bayesian model with an average area under curve (AUC) value of 0.944 was finally selected. We found that nimesulide exhibited strong binding affinity to CYBB and HSP90AB1, and experimentally verified that nimesulide reduced the expression of RIPK3 and CYBB, suggesting its potential as an inhibitor of chondrocyte necroptosis. Furthermore, scRNA-seq results showed that necroptosis in OA was significantly upregulated on regulatory chondrocytes (RegC) compared to other chondrocyte subtypes.
The results indicate that nimesulide might be used to treat OA by inhibiting chondrocyte necroptosis through down-regulation of RIK3 and CYBB genes. This study reveals the role of chondrocyte necroptosis in OA, and suggests a potential therapeutic strategy by regulating necroptosis with nimesulide.
骨关节炎（OA）是最常见的关节疾病形式，其特征为软骨退变。最近的研究表明，OA的发病机制与软骨细胞坏死性凋亡有关。
在本研究中，我们使用单细胞RNA测序（scRNA-seq）和批量RNA测序数据来分析OA软骨细胞中的坏死性凋亡调控。我们进行了富集分析、实验验证、构建机器学习模型并对接药物分子。
经过最小绝对收缩和选择算子（LASSO）算法筛选，获得了4个具有诊断特征的枢纽基因（RIPK3、CYBB、HSP90AB1和TRAF5）。在比较多个模型后，最终选择了平均曲线下面积（AUC）值为0.944的贝叶斯模型。我们发现尼美舒利对CYBB和HSP90AB1表现出很强的结合亲和力，并通过实验验证尼美舒利降低了RIPK3和CYBB的表达，表明其作为软骨细胞坏死性凋亡抑制剂的潜力。此外，scRNA-seq结果显示，与其他软骨细胞亚型相比，OA中坏死性凋亡在调节性软骨细胞（RegC）上显著上调。
结果表明，尼美舒利可能通过下调RIK3和CYBB基因来抑制软骨细胞坏死性凋亡，从而用于治疗OA。本研究揭示了软骨细胞坏死性凋亡在OA中的作用，并提出了通过尼美舒利调节坏死性凋亡的潜在治疗策略。
