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Cylindromatosis (CYLD) is a deubiquitinating enzyme that regulates multiple key signaling pathways involved in the pathophysiology of knee osteoarthritis (KOA). Previous studies have indicated that the expression of CYLD in the articular cartilage of patients with KOA is significantly higher than in healthy controls. However, limited data are available regarding the association between CYLD expression and the severity of KOA. The aim of the present study was to investigate the association between CYLD expression in joint tissues and the severity of KOA. A total of 156 individual tibial plateau samples were obtained between January 2011 and January 2016 from patients that had undergone total knee arthroplasty due to KOA or from healthy controls. The severity of KOA was evaluated using the Kellgren Lawrence (KL) and Mankin scoring systems. Additionally, CYLD expression in the articular cartilage and subchondral bone was analyzed using immunohistochemistry. Compared with the healthy controls, patients with KOA exhibited significantly increased CYLD levels in the articular cartilage (6.53±2.01 vs. 28.69±13.23, P<0.001) and significantly decreased CYLD levels in the subchondral bone (11.46±2.34 vs. 3.50±2.54, P<0.001). Correlation analysis indicated that CYLD expression in the articular cartilage was positively correlated with the KL (r=0.837, P<0.001) and Mankin scores (r=0.925, P<0.001), while its expression in the subchondral bone was negatively correlated with the KL (r=-0.802, P<0.001) and Mankin scores (r=-0.844, P<0.001). The results of the present study demonstrate that CYLD levels in the articular cartilage and subchondral bone are associated with the severity of KOA. Thus, CYLD may be a potential diagnostic and predictive biomarker for KOA and a novel target in its treatment. [ABSTRACT FROM AUTHOR]