Objectives The aim of this study was to identify biomarkers for radiographic osteoarthritis severity and progression acting within the inflammation and metabolic pathways. Methods For 3,517 Rotterdam Study participants, 184 plasma protein levels were measured using Olink inflammation and cardiometabolic panels. We studied associations with severity and progression of knee, hip, hand osteoarthritis, and a composite overall OA burden-score by multivariable regression models, adjusting for age, sex, cell counts and BMI. Results We found 18 significantly associated proteins for overall osteoarthritis burden, of which 5 stayed significant after multiple testing correction: circulating Cartilage acidic protein 1 (CRTAC1), Cartilage oligomeric matrix protein (COMP), Thrombospondin 4 (THBS4), Interleukin 18 receptor 1 (IL18R1) and Tumor necrosis factor ligand superfamily member 14 (TNFSF14). These proteins were also associated with progression of knee OA, with the exception of IL18R1. The strongest association was found for the level of CRTAC1 with 1 SD increase in protein level resulting in an increase of 0.09 (95%CI : 0.06–0.12) in overall osteoarthritis KLsum-score (p= 2.9x10−8), in the model adjusted for age, sex, BMI and cell counts. This association was also present with severity of osteoarthritis in all three joints, progression of knee osteoarthritis and was independent of BMI. We observed a stronger association for CRTAC1 with osteoarthritis than for the well-known osteoarthritis-biomarker COMP. Conclusion We identified several compelling biomarkers reflecting overall osteoarthritis burden and increased risk for osteoarthritis progression. CRTAC1 was the most compelling and robust biomarker for osteoarthritis severity and progression. Such a biomarker may be used for disease monitoring.

中文翻译：

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血浆蛋白质组学将 CRTAC1 鉴定为骨关节炎严重程度和进展的生物标志物

目标 本研究的目的是确定在炎症和代谢途径中起作用的影像学骨关节炎严重程度和进展的生物标志物。方法 对于 3,517 名鹿特丹研究参与者，使用 Olink 炎症和心脏代谢面板测量了 184 种血浆蛋白水平。我们通过多变量回归模型研究了膝关节、髋关节、手部骨关节炎的严重程度和进展以及综合总体 OA 负担评分的关联，并针对年龄、性别、细胞计数和 BMI 进行了调整。结果 我们发现了 18 种与总体骨关节炎负担显着相关的蛋白质，其中 5 种在多次测试校正后仍然显着：循环软骨酸性蛋白 1 (CRTAC1)、软骨寡聚基质蛋白 (COMP)、血小板反应蛋白 4 (THBS4)、白细胞介素 18 受体 1 (IL18R1) 和肿瘤坏死因子配体超家族成员 14 (TNFSF14)。除 IL18R1 外，这些蛋白质还与膝关节 OA 的进展相关。在模型中，CRTAC1 水平与蛋白质水平增加 1 SD 的关联最强，导致整体骨关节炎 KLsum 评分增加 0.09 (95%CI：0.06–0.12) (p= 2.9x10-8)根据年龄、性别、BMI 和细胞计数进行调整。这种关联也与所有三个关节的骨关节炎严重程度、膝骨关节炎的进展有关，并且与 BMI 无关。我们观察到 CRTAC1 与骨关节炎的关联比众所周知的骨关节炎生物标志物 COMP 更强。结论 我们确定了几种引人注目的生物标志物，它们反映了总体骨关节炎负担和骨关节炎进展风险增加。CRTAC1 是骨关节炎严重程度和进展的最引人注目和最强大的生物标志物。这样的生物标志物可用于疾病监测。