Osteoarthritis as a systemic disorder: multi-organ crosstalk in pathogenesis and therapeutic targeting.

While osteoarthritis (OA) has long been viewed primarily as a localized, mechanically-driven joint disorder, emerging evidence suggests that systemic factors may play a significant modulating role in its pathogenesis. This review presents the "Gut-Brain-Liver-Kidney axis" as a potential regulatory framework to explore a conceptual shift towards a systemic perspective on this traditionally localized disease. Available evidence is synthesized to clarify how gut microbiota dysbiosis and its metabolites contribute to systemic inflammation and disrupt joint homeostasis through specific pathways, such as the GUDCA-FXR-GLP-1 axis. Bacterial extracellular vesicles are further highlighted as essential nanoscale messengers facilitating communication between the gut and joints. Extending beyond gut health, the significant impact of central sensitization and neuroendocrine dysregulation in the brain is investigated as a key driver of chronic pain perception-a phenomenon often disproportionate to observable structural damage. Unlike mechanisms that directly cause cartilage breakdown, central sensitization primarily modulates pain experience and can secondarily influence disease progression by promoting maladaptive behaviors (e.g., reduced mobility). The liver's involvement is also analyzed, particularly its disorders related to iron and lipid metabolism that promote chondrocyte ferroptosis. Furthermore, the analysis addresses how renal dysfunction intensifies OA by impairing vitamin D metabolism and leading to the accumulation of uremic toxins, such as indoxyl sulfate. By integrating these interconnected systemic pathways, a complex network of potential novel therapeutic targets is revealed. Consequently, innovative strategies aimed at these axes are outlined, including the use of probiotics, vagus nerve stimulation, FGF21, GalNAc-siRNA, and vitamin D supplementation. This perspective encourages moving beyond symptom management toward mechanism-based, multi-targeted strategies. Key unanswered questions are outlined and priorities for future research and clinical translation in this evolving field are proposed.