Identification of novel biomarkers for arthrofibrosis after total knee arthroplasty in animal models and clinical patients

BACKGROUND: Arthrofibrosis is a debilitating complication after total knee arthroplasty (TKA) which becomes a considerable burden for both patients and clinical practitioners. Our study aimed to identify novel biomarkers and therapeutic targets for drug discovery. METHODS: Potential biomarker genes were identified based on bioinformatic analysis. Twelve male New Zealand white rabbits underwent surgical fixation of unilateral knees to mimics the joint immobilization of the clinical scenario after TKA surgery. Macroscopic assessment, hydroxyproline content determination, and histological analysis of tissue were performed separately after 3-days, 1-week, 2-weeks, and 4-weeks of fixation. We also enrolled 46 arthrofibrosis patients and 92 controls to test the biomarkers. Clinical information such as sex, age, range of motion (ROM), and visual analogue scale (VAS) was collected by experienced surgeons FINDINGS: Base on bioinformatic analysis, transforming growth factor-beta receptor 1 (TGFBR1) was identified as the potential biomarkers. The level of TGFBR1 was significantly raised in the rabbit synovial tissue after 4-weeks of fixation (p<0.05). TGFBR1 also displayed a highly positive correlation with ROM loss and hydroxyproline contents in the animal model. TGFBR1 showed a significantly higher expression level in arthrofibrosis patients with a receiver operating characteristic (ROC) area under curve (AUC) of 0.838. TGFBR1 also performed positive correlations with VAS baseline (0.83) and VAS after 1 year (0.76) while negatively correlated with ROM baseline (-0.76) in clinical patients. INTERPRETATION: Our findings provided novel biomarkers for arthrofibrosis diagnosis and uncovered the role of TGFBR1. This may contribute to arthrofibrosis prevention and therapeutic drug discovery.