Hand osteoarthritis is a common heterogeneous joint disorder with unclear molecular mechanisms and no disease-modifying drugs. In this study, we performed single-cell RNA sequencing analysis to compare the cellular composition and subpopulation-specific gene expression between cartilage with macroscopically confirmed osteoarthritis (n = 5) and cartilage without osteoarthritis (n = 5) from the interphalangeal joints of five donors. Of 105 142 cells, we identified 13 subpopulations, including a novel subpopulation with inflammation-modulating potential annotated as inflammatory chondrocytes. Fibrocartilage chondrocytes exhibited extensive alteration of gene expression patterns in osteoarthritic cartilage compared with nonosteoarthritic cartilage. Both inflammatory chondrocytes and fibrocartilage chondrocytes showed a trend toward increased numbers in osteoarthritic cartilage. In these two subpopulations from osteoarthritic cartilage, the ferroptosis pathway was enriched, and expression of iron overload-related genes, e.g., FTH1, was elevated. To verify these findings, we conducted a Mendelian randomization study using UK Biobank and a population-based cross-sectional study using data collected from Xiangya Osteoarthritis Study. Genetic predisposition toward higher expression of FTH1 mRNA significantly increased the risk of hand osteoarthritis (odds ratio = 1.07, 95% confidence interval: 1.02–1.11) among participants (n = 332 668) in UK Biobank. High levels of serum ferritin (encoded by FTH1), a biomarker of body iron overload, were significantly associated with a high prevalence of hand osteoarthritis among participants (n = 1 241) of Xiangya Osteoarthritis Study (P-for-trend = 0.037). In conclusion, our findings indicate that inflammatory and fibrocartilage chondrocytes are key subpopulations and that ferroptosis may be a key pathway in hand osteoarthritis, providing new insights into the pathophysiology and potential therapeutic targets of hand osteoarthritis.

手部骨关节炎是一种常见的异质性关节疾病，分子机制尚不清楚，也没有缓解疾病的药物。在这项研究中，我们进行了单细胞 RNA 测序分析，比较了来自 5 名捐赠者指间关节的肉眼证实的骨关节炎软骨 ( n  = 5) 和无骨关节炎软骨 ( n  = 5) 之间的细胞组成和亚群特异性基因表达。在 105 142 个细胞中，我们鉴定了 13 个亚群，其中包括一种具有炎症调节潜力的新亚群，被注释为炎症软骨细胞。与非骨关节炎软骨相比，纤维软骨软骨细胞在骨关节炎软骨中表现出基因表达模式的广泛改变。骨关节炎软骨中炎性软骨细胞和纤维软骨细胞都显示出数量增加的趋势。在这两个来自骨关节炎软骨的亚群中，铁死亡途径丰富，并且铁过载相关基因（例如FTH1）的表达升高。为了验证这些发现，我们利用英国生物样本库进行了孟德尔随机研究，并利用湘雅骨关节炎研究收集的数据进行了基于人群的横断面研究。 英国生物银行的参与者 ( n = 332 668) 中FTH1 mRNA高表达的遗传倾向显着增加了手部骨关节炎的风险（比值比 = 1.07，95% 置信区间：1.02–1.11） 。 湘雅骨关节炎研究参与者 ( n = 1 241) 中高水平的血清铁蛋白（FTH1编码）是体内铁超载的生物标志物，与手部骨关节炎的高患病率显着相关（趋势P = 0.037）。总之，我们的研究结果表明炎症软骨细胞和纤维软骨细胞是关键亚群，铁死亡可能是手部骨关节炎的关键途径，为手部骨关节炎的病理生理学和潜在治疗靶点提供了新的见解。