Classification of four distinct osteoarthritis subtypes with a knee joint tissue transcriptome atlas.
Classification of four distinct osteoarthritis subtypes with a knee joint tissue transcriptome atlas.
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使用膝关节组织转录组图谱对四种不同的骨关节炎亚型进行分类
DOI：
10.1038/s41413-020-00109-x
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发表时间：
2020-11-12
期刊：
影响因子：
12.7
通讯作者：
Ouyang H
中科院分区：
文献类型：
--
作者：
Yuan C;Pan Z;Zhao K;Li J;Sheng Z;Yao X;Liu H;Zhang X;Yang Y;Yu D;Zhang Y;Xu Y;Zhang ZY;Huang T;Liu W;Ouyang H
骨关节炎（OA）有限的分子分类和疾病特征阻碍了OA患者的预诊断和靶向治疗的发展。为了分类和理解OA的亚型，我们从多个临床中心收集了三种类型的组织，包括软骨、软骨下骨和滑膜，并构建了OA患者的广泛转录组图谱。通过对软骨转录组进行无监督聚类分析，OA患者被分为四种具有不同分子特征的亚型：糖胺聚糖代谢紊乱亚型（C1）、胶原代谢紊乱亚型（C2）、激活的感觉神经元亚型（C3）和炎症亚型（C4）。通过对三种膝关节组织类型的配体-受体串扰分析，我们将分子功能与不同OA亚型的临床症状联系起来。例如，脉管系统发育的基因本体功能术语在C2的软骨下骨-软骨串扰和C4的软骨-软骨下骨串扰中富集，这可能导致C2患者中严重的骨赘和C4患者中明显的关节间隙狭窄。基于本研究中确定的四种OA亚型的标记基因，我们通过随机森林分类，用两个独立的已发表的RNA-seq数据集对OA亚型进行建模。这项工作的发现与传统的OA诊断相矛盾，通过医学影像学，揭示了不同的分子亚型在膝关节OA患者，这可能允许精确的诊断和治疗OA。
The limited molecular classifications and disease signatures of osteoarthritis (OA) impede the development of prediagnosis and targeted therapeutics for OA patients. To classify and understand the subtypes of OA, we collected three types of tissue including cartilage, subchondral bone, and synovium from multiple clinical centers and constructed an extensive transcriptome atlas of OA patients. By applying unsupervised clustering analysis to the cartilage transcriptome, OA patients were classified into four subtypes with distinct molecular signatures: a glycosaminoglycan metabolic disorder subtype (C1), a collagen metabolic disorder subtype (C2), an activated sensory neuron subtype (C3), and an inflammation subtype (C4). Through ligand-receptor crosstalk analysis of the three knee tissue types, we linked molecular functions with the clinical symptoms of different OA subtypes. For example, the Gene Ontology functional term of vasculature development was enriched in the subchondral bone-cartilage crosstalk of C2 and the cartilage-subchondral bone crosstalk of C4, which might lead to severe osteophytes in C2 patients and apparent joint space narrowing in C4 patients. Based on the marker genes of the four OA subtypes identified in this study, we modeled OA subtypes with two independent published RNA-seq datasets through random forest classification. The findings of this work contradicted traditional OA diagnosis by medical imaging and revealed distinct molecular subtypes in knee OA patients, which may allow for precise diagnosis and treatment of OA.
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