Division of Rheumatology, Department of Internal Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, South Korea.
Department of Pathology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, South Korea.
Front Immunol. 2022 Aug 18;13:901555. doi: 10.3389/fimmu.2022.901555. eCollection 2022.
Pyruvate kinase M2 (PKM2) is an enzyme that regulates the final process of glycolysis and exists in tetrameric and dimeric forms. The dimeric form of PKM2, also known as tumour M2-PK, increases when aerobic glycolysis is augmented, a feature observed in rheumatoid arthritis (RA). We investigated whether plasma tumour M2-PK is elevated in patients with RA and whether its levels correlate with disease activity.
Plasma levels of tumour M2-PK were measured for patients with RA (n=151), those with osteoarthritis (OA) (n=37), and controls (n=37). We evaluated the association between plasma tumour M2-PK and continuous variables using Pearson's correlation analysis, and multivariate logistic regression analysis to determine the association between plasma tumour M2-PK and disease activity status. Knee synovial tissue blocks from patients with RA and OA were subjected to real-time quantitative PCR (qPCR) using two different primers for PKM2 and tumour M2-PK immunohistochemical (IHC) staining.
The tumour M2-PK level significantly correlated with the disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) (r=0.546, p<0.001) and DAS28-C-reactive protein (CRP) (r=0.589, p<0.001). Moreover, repeat testing of tumour M2-PK levels in 20 patients revealed a significant decline in tumour M2-PK levels after reduction in inflammation (p<0.001). Area under the receiver operating characteristic curve (AUROC) analysis demonstrated that upon incorporation of tumour M2-PK, ESR, and CRP, the area under the curve was 0.962 for distinguishing moderate/high from remission/low disease activity. Adjusted logistic regression also revealed that a tumour M2-PK >43.9 U/mL (OR 3.672, p=0.042) independently predicted moderate/high disease activity status. Furthermore, tumour M2-PK levels in patients with RA were significantly higher than in those with OA and controls (all p<0.001). However, no differences were found in PKM2 expression in RA and OA synovial tissues as assessed by qPCR, and IHC analysis revealed negligible tumour M2-PK expression in the synovial tissues.
Circulating plasma tumour M2-PK levels may be a clinically useful indicator for evaluating disease activity and RA diagnosis.
丙酮酸激酶 M2（PKM2）是调节糖酵解最后过程的一种酶，存在四聚体和二聚体两种形式。当有氧糖酵解增加时，PKM2 的二聚体形式（也称为肿瘤 M2-PK）增加，这在类风湿关节炎（RA）中观察到。我们研究了 RA 患者血浆肿瘤 M2-PK 是否升高，以及其水平是否与疾病活动度相关。
测量了 151 例 RA 患者、37 例骨关节炎（OA）患者和 37 例对照组的血浆肿瘤 M2-PK 水平。我们使用 Pearson 相关分析评估了血浆肿瘤 M2-PK 与连续变量之间的关系，并使用多变量逻辑回归分析确定了血浆肿瘤 M2-PK 与疾病活动状态之间的关系。使用两种不同的 PKM2 引物和肿瘤 M2-PK 免疫组织化学（IHC）染色对 RA 和 OA 患者的膝关节滑膜组织块进行实时定量 PCR（qPCR）。
肿瘤 M2-PK 水平与 28 关节疾病活动评分（DAS28）-红细胞沉降率（ESR）（r=0.546，p<0.001）和 DAS28-C 反应蛋白（CRP）（r=0.589，p<0.001）显著相关。此外，对 20 例患者的肿瘤 M2-PK 水平进行重复检测后发现，炎症减轻后肿瘤 M2-PK 水平显著下降（p<0.001）。受试者工作特征曲线（ROC）下面积（AUROC）分析表明，在纳入肿瘤 M2-PK、ESR 和 CRP 后，区分中/高度疾病活动与缓解/低度疾病活动的曲线下面积为 0.962。调整后的逻辑回归也表明，肿瘤 M2-PK>43.9 U/mL（OR 3.672，p=0.042）可独立预测中/高度疾病活动状态。此外，RA 患者的肿瘤 M2-PK 水平明显高于 OA 患者和对照组（均 p<0.001）。然而，qPCR 评估 RA 和 OA 滑膜组织中 PKM2 表达无差异，IHC 分析显示滑膜组织中肿瘤 M2-PK 表达可忽略不计。
循环血浆肿瘤 M2-PK 水平可能是评估疾病活动度和 RA 诊断的一种有临床价值的指标。
