XJB-5-131 protects chondrocytes from ferroptosis to alleviate osteoarthritis progression via restoring Pebp1 expression

• Published in: Journal of orthopaedic translation Vol. 44; pp. 114 - 124
• Main Authors: Sun, Wei, Lv, Zhongyang, Li, Weitong, Lu, Jun, Xie, Ya, Wang, Peng, Jiang, Ruiyang, Dong, Jian, Guo, Hu, Liu, Zizheng, Fei, Yuxiang, Tan, Guihua, Wang, Maochun, Ren, Kewei, Xu, Jun, Sun, Huiqing, Jiang, Xuefeng, Shi, Dongquan
• Format: Journal Article
• Language: English
• Published: Singapore Elsevier B.V 01.01.2024; Chinese Speaking Orthopaedic Society; Elsevier
• Subjects: Cartilage degeneration; Ferroptosis; Original; Osteoarthritis; XJB-5-131; XJB-5-131; Ferroptosis; Cartilage degeneration; Osteoarthritis
• ISSN: 2214-031X; 2214-0328
• DOI: 10.1016/j.jot.2023.12.005

Osteoarthritis (OA) is the most common age-related musculoskeletal disease. However, there is still a lack of therapy that can modify OA progression due to the complex pathogenic mechanisms. The aim of the study was to explore the role and mechanism of XJB-5-131 inhibiting chondrocytes ferroptosis to alleviate OA progression. We treated tert-butyl hydroperoxide (TBHP)-induced ferroptosis of mouse primary chondrocytes with XJB-5-131 in vitro. The intracellular ferroptotic hallmarks, cartilage anabolic and catabolic markers, ferroptosis regulatory genes and proteins were detected. Then we established a mouse OA model via destabilization of the medial meniscus (DMM) surgery. The OA mice were treated with intra-articular injection of XJB-5-131 regularly (2 μM, 3 times per week). After 4 and 8 weeks, we performed micro-CT and histological examination to evaluate the protection role of XJB-5-131 in mouse OA subjects. RNA sequencing analysis was performed to unveil the key downstream gene of XJB-5-131 exerting the anti-ferroptotic effect in OA. XJB-5-131 significantly suppressed TBHP-induced increases of ferroptotic hallmarks (ROS, lipid peroxidation, and Fe2+ accumulation), ferroptotic drivers (Ptgs2, Pgd, Tfrc, Atf3, Cdo1), while restored the expression of ferroptotic suppressors (Gpx4, Fth1). XJB-5-131 evidently promoted the expression of cartilage anabolic and decreased the expression of cartilage catabolic markers. Moreover, intra-articular injection of XJB-5-131 significantly inhibited the expression of Cox2 and Mmp13, while promoted the expression of Col2a1, Gpx4 and Fth1 in DMM-induced mouse articular cartilage. Further, we identified Pebp1 as a potential target of XJB-5-131 by RNA sequencing analysis. The anti-ferroptosis and chondroprotective effects of XJB-5-131 were significantly diminished by Locostatin, a specific antagonist of Pebp1. XJB-5-131 significantly protects chondrocytes from ferroptosis in TBHP-induced mouse primary chondrocytes and DMM surgery-induced OA mice model via restoring the expression of Pebp1. XJB-5-131 is a potential therapeutic drug in the management of OA progression. [Display omitted]