O-GlcNAc transferase influences the progression of degenerative cartilage disease in lumbar facet joint osteoarthritis through FoxO1 and EGR1.

This study aimed to investigate the role of the O-GlcNAc transferase (OGT)/Forkhead Box O1 (FoxO1) signaling axis in age-induced facet joint osteoarthritis (FJOA) and its impact on chondrocyte homeostasis. Using a mouse model, the effects of OGT knockout on cartilage integrity in facet joints were examined. Molecular assays were conducted to analyze OGT's influence on FoxO1 expression and its stability against ubiquitin-mediated degradation. In vitro studies with chondrocytes were performed to assess the impact of FoxO1 overexpression on extracellular matrix synthesis, while in vivo experiments were carried out to test the protective effects of FoxO1 overexpression on FJOA progression. Additionally, the functionality of ATDC5 cells and the regulation of EGR1 by the OGT/FoxO1 axis were evaluated. OGT knockout led to exacerbated cartilage degeneration in facet joints, promoting age-related FJOA. OGT was found to stabilize FoxO1 protein by amplifying its expression and preventing its degradation. The T627 site on FoxO1, along with other key sites (T317, S550, T648, S654), was identified as essential for FoxO1's stability and transcriptional activity upon OGT overexpression. Elevated FoxO1 levels counteracted OGT deficiency in chondrocytes, enhancing extracellular matrix synthesis. In vivo, FoxO1 overexpression mitigated FJOA progression and chondrocyte apoptosis due to OGT deficiency. The OGT/FoxO1 signaling also regulated EGR1 expression, impacting ATDC5 cell function. Collectively, the OGT/FoxO1/EGR1 axis plays a critical role in maintaining chondrocyte homeostasis and protecting facet joint integrity, suggesting a potential therapeutic target for age-related FJOA and cartilage degeneration.