LOXL1、THY1和TYMS定义了骨关节炎软骨中注释衍生的血红蛋白相关免疫转录组特征
LOXL1, THY1, and TYMS define an annotation-derived hemoglobin-associated immunotranscriptomic signature in osteoarthritis cartilage.
摘要(中文译文)
骨关节炎（OA）日益被认为是一种累及全关节的疾病，涉及软骨退变、滑膜炎症、软骨下骨重塑以及免疫相关炎症信号传导。非红系血红蛋白（Hb）相关转录程序近年来被认为参与软骨细胞的缺氧适应，但其与OA软骨中免疫相关转录组重塑的关系仍不清楚。本研究旨在识别OA软骨中注释来源的Hb相关转录组生物标志物，并表征其与推断的免疫相关转录组特征之间的关联。从基因表达综合数据库（GEO）整合人类软骨转录组数据集以构建统一的训练队列，并使用独立数据集进行外部验证。在批次效应校正后，将OA差异表达基因与GeneCards来源的Hb相关注释基因集取交集。应用加权基因共表达网络分析，结合最小绝对收缩和选择算子及其他互补机器学习方法，以识别核心Hb相关OA基因。构建多变量逻辑回归列线图，并通过跨队列的受试者工作特征分析进行评估。使用GSVA、CIBERSORT、ssGSEA和相关性分析推断免疫通路活性和免疫细胞相关转录组特征。在白细胞介素-1β刺激的炎症软骨细胞模型中使用qRT-PCR进行实验验证。通过整合转录组分析识别出三个Hb相关核心基因——LOXL1、THY1和TYMS，其在训练队列和独立验证队列的OA软骨中均持续上调。免疫谱分析提示OA软骨存在免疫激活的转录组状态，其特征为巨噬细胞相关信号增加、静息NK细胞和CD4记忆T细胞减少、活化免疫细胞特征升高以及抗原呈递相关和免疫调节相关功能增强。这些Hb相关核心基因的表达与巨噬细胞和活化T细胞相关特征及抗原呈递相关免疫功能呈强正相关。基于这三个基因的列线图在跨队列中表现出高判别性能，训练队列中AUC为0.974。在IL-1β刺激的C28/I2软骨细胞模型中的qRT-PCR支持LOXL1、THY1和TYMS的炎症诱导性。本研究确定LOXL1、THY1和TYMS为OA软骨中可重复的注释来源Hb相关组织水平转录组生物标志物。其表达与巨噬细胞和活化T细胞相关转录组特征相关，为注释来源的Hb相关基因程序与OA免疫重塑之间提供了免疫转录组学联系。
Abstract
Osteoarthritis (OA) is increasingly recognized as a whole-joint disease involving cartilage degeneration, synovial inflammation, subchondral bone remodeling, and immune-associated inflammatory signaling. Non-erythroid hemoglobin (Hb)-associated transcriptional programs have recently been implicated in chondrocyte hypoxic adaptation, but their relationship with immune-associated transcriptomic remodeling in OA cartilage remains unclear. This study aimed to identify annotation-derived Hb-associated transcriptomic biomarkers in OA cartilage and to characterize their associations with inferred immune-related transcriptomic features. Human cartilage transcriptomic datasets were integrated from Gene Expression Omnibus (GEO) to construct a harmonized training cohort, with independent datasets used for external validation. After batch-effect correction, OA differentially expressed genes were intersected with a GeneCards-derived Hb-associated annotation gene set. Weighted gene co-expression network analysis, together with the least absolute shrinkage and selection operator and other complementary machine-learning approaches, was applied to identify hub Hb-associated OA genes. A multivariable logistic-regression nomogram was constructed and evaluated by receiver operating characteristic analysis across cohorts. Immune pathway activity and immune-cell-associated transcriptomic signatures were inferred using GSVA, CIBERSORT, ssGSEA, and correlation analyses. Experimental validation was performed using qRT-PCR in an interleukin-1β-stimulated inflammatory chondrocyte model. Three Hb-associated hub genes-LOXL1, THY1, and TYMS-were identified through integrative transcriptomic analysis and consistently upregulated in OA cartilage across training and independent validation cohorts. Immune profiling suggested an immune-activated transcriptomic state in OA cartilage, characterized by increased macrophage-associated signals, reduced resting NK and CD4 memory T cells, elevated activated immune cell signatures, and enhanced antigen presentation-related and immune regulation-related functions. Expression of these Hb-associated hub genes showed strong positive correlations with macrophage- and activated T-cell-related signatures and antigen presentation-associated immune functions. A nomogram based on the three genes demonstrated high discriminative performance across cohorts, with an AUC of 0.974 in the training cohort. qRT-PCR in an IL-1β-stimulated C28/I2 chondrocyte model supported the inflammatory inducibility of LOXL1, THY1, and TYMS. This study identifies LOXL1, THY1, and TYMS as reproducible annotation-derived Hb-associated tissue-level transcriptomic biomarkers in OA cartilage. Their expression is associated with macrophage- and activated T-cell-related transcriptomic signatures, providing an immunotranscriptomic link between annotation-derived Hb-associated gene programs and immune remodeling in OA.
如何引用
AMA
Xin Zhang, Zhaochen Ye, Zheng Qin, Yizhe Li, Zhilong Jing, Dawei Yang. LOXL1, THY1, and TYMS define an annotation-derived hemoglobin-associated immunotranscriptomic signature in osteoarthritis cartilage.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1823558.
APA
Xin Zhang, Zhaochen Ye, Zheng Qin, Yizhe Li, Zhilong Jing, Dawei Yang (2026). LOXL1, THY1, and TYMS define an annotation-derived hemoglobin-associated immunotranscriptomic signature in osteoarthritis cartilage.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1823558
GB/T 7714
Xin Zhang, Zhaochen Ye, Zheng Qin, Yizhe Li, Zhilong Jing, Dawei Yang. LOXL1, THY1, and TYMS define an annotation-derived hemoglobin-associated immunotranscriptomic signature in osteoarthritis cartilage.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1823558.
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