TL1A(TNFSF15)-ENO1 axis promotes osteoarthritis by disrupting redox homeostasis via the PI3K/AKT pathway

Osteoarthritis (OA) is characterized by cartilage degeneration, oxidative stress, and chondrocyte senescence. This study investigated whether TL1A promotes OA through ENO1-associated redox, senescence and PI3K-AKT signaling mechanisms.

Human paired OA cartilage, primary chondrocytes, and mouse age-associated and destabilization of the medial meniscus (DMM)-induced OA models were used. TL1A and ENO1 were manipulated using genetic deletion, intra-articular adenoviral delivery, and siRNA-mediated silencing. Oxidative stress, cellular senescence, cartilage degeneration, ENO1-related regulatory mechanisms, and PI3K-AKT activation were assessed using histology, immunostaining, Western blotting, qPCR, RNA-seq, co-immunoprecipitation, ubiquitination assays, and pharmacological rescue experiments.

TL1A-positive chondrocytes were increased in damaged versus paired undamaged human cartilage (n = 8 paired patients) [mean paired difference, +64.24 percentage points; 95% CI, 57.80-70.68]. In DMM mice, Tl1a deletion reduced cartilage damage [OARSI Hodges-Lehmann (HL) difference, -2.50; 95% CI, -4 to 0], whereas intra-articular Tl1a overexpression induced mild OA-like cartilage changes [OARSI HL difference, +0.75; 95% CI, 0-1.50]. TL1A silencing reduced ROS fluorescence in IL-1β-treated human chondrocytes [mean change, -53.50%; 95% CI, -61.59 to -45.41]. TL1A interacted with ENO1 and was associated with altered ENO1 ubiquitination and protein abundance; Eno1 overexpression restored OA severity in DMM-operated Tl1a^-/- mice [OARSI HL difference, +3.75; 95% CI, 3-5.50]. PI3K-AKT activation contributed to this phenotype, as 740 Y-P increased OARSI scores in DMM-operated Tl1a^-/- mice [HL difference, +1.25; 95% CI, 0-2.50].

TL1A contributes to OA progression by promoting ENO1-associated redox imbalance, chondrocyte senescence, and PI3K-AKT signaling, supporting the TL1A-ENO1 axis as a potential therapeutic target.