Semaglutide reverses GAPDH downregulation, reduces senescence markers in osteoarthritis chondrocytes

Osteoarthritis (OA) is a debilitating joint disease characterized by progressive cartilage degradation and chondrocyte dysfunction. A key pathological feature is chondrocyte senescence, where cells lose proliferative capacity and secrete pro-inflammatory factors, accelerating disease progression. Current treatments primarily manage symptoms, failing to halt or reverse cartilage damage. The GLP-1 receptor pathway, traditionally known for its role in glucose homeostasis, has recently garnered interest for its anti-inflammatory and cytoprotective effects, suggesting a potential therapeutic avenue for OA by targeting chondrocyte health and senescence.

Researchers collected transcriptomic data from OA and control chondrocytes, correcting batch effects with Harmony and performing differential expression analysis using DESeq2. Functional enrichment was assessed via KEGG and GSEA, while WGCNA and PPI networks identified key OA-related modules and hub genes. In vitro experiments on chondrocytes included ROS detection, RT-PCR, and ELISA to measure oxidative stress, inflammatory mediators, and senescence markers. Cell proliferation was evaluated using CCK-8, and cells were treated with semaglutide at different concentrations to verify its regulatory effects on the identified pathways and markers.

Transcriptomic analysis revealed significant upregulation of inflammatory and oxidative stress pathways in OA chondrocytes, alongside downregulation of cell cycle and DNA repair pathways, indicating an accumulation of senescent cells. WGCNA and PPI network analyses identified GAPDH as a key hub gene, with its expression markedly reduced in OA chondrocytes. In vitro validation confirmed that OA cells exhibited decreased proliferative capacity, elevated ROS levels, and increased expression of p53, IL-6, and TGF-β. These findings collectively point to a glycolysis-senescence axis mediated by GAPDH in OA progression. Semaglutide treatment effectively reversed the downregulation of GAPDH expression, improved chondrocyte proliferation, and significantly reduced the levels of p53 and key inflammatory cytokines, including IL-6 and TGF-β.