Oxidative stress arises from disrupted equilibrium between reactive oxygen species generation and cellular antioxidant capacity, serving as a pivotal mechanism in inflammatory pathology, particularly osteoarthritis development. The progression of osteoarthritis-related pain may additionally involve oxidative stress through its activation of nociceptive signaling pathways, but the mechanism of its influence on the progression of osteoarthritis is not yet unanimous. The study utilized publicly available sequencing data, which included specimens from patients with osteoarthritis and matched healthy controls, retrieved from GEO database, and combined them after removing batch effects. A multi-step analytical approach was employed to identify pivotal diagnostic biomarkers for osteoarthritis. This strategy encompassed examining differential gene expression, constructing protein-protein interaction networks, applying machine learning algorithms, and assessing co-expression patterns. Subsequently, a diagnostic framework incorporating a nomogram was developed based on these candidate genes. To discern distinct patient subgroups, cluster analysis was conducted. Further investigations into the underlying biology revealed divergent functional pathways and immune cell infiltration landscapes across the identified subtypes, highlighting the putative roles of the key biomarkers. We investigated the effects of FKBP5 on osteoarthritis through both in vivo and in vitro experiments, examining chondrocyte proliferation capacity, apoptosis, cellular senescence, mitochondrial function, and cartilage degeneration. We successfully screened the key genes PPARGC1A, FKBP5, and MMP13 for the diagnosis of osteoarthritis, constructed a diagnostic model and a nomogram of osteoarthritis, and verified their excellent diagnostic ability. Based on these core genes we classified osteoarthritis into two subtypes. Enrichment analysis and immune infiltration analysis confirmed that FKBP5 regulates the immune microenvironment in osteoarthritis and influences the progression of osteoarthritis. Both in vivo and in vitro experiments confirmed that FKBP5 overexpression enhances chondrocyte viability, proliferative capacity, and mitochondrial function under inflammatory conditions, while reducing cellular senescence, apoptosis, and cartilage degeneration. FKBP5 may serve as a potential therapeutic target for osteoarthritis intervention. Our study identified distinct molecular subtypes of osteoarthritis by analyzing genes associated with oxidative stress. Furthermore, we found that FKBP5 exerts a positive regulatory effect on chondrocyte function and mitigates cartilage degeneration in the osteoarthritis environment. This provides new insights for personalized treatment of osteoarthritis.
Huang et al. (Tue,) studied this question.