Restoring adenosine balance in axial spondyloarthritis: a stage-specific framework for immune and structural modulation

Axial Spondyloarthritis (AS) is a chronic immune-mediated disease of the axial skeleton characterized by persistent inflammation and pathological bone formation driven by reciprocal signaling between immune and stromal cells. Central to this interplay is adenosine-a key metabolic regulator of immune tolerance and tissue remodeling. In AS, purinergic homeostasis is profoundly disrupted: the ectonucleotidases CD39 and CD73, responsible for adenosine synthesis, are downregulated, while adenosine-degrading enzymes ADA and its surface anchor CD26 are upregulated. This enzymatic disequilibrium depletes adenosine in inflamed tissues, impairs FOXP3⁺ regulatory T cell induction, and amplifies Th17-driven inflammation and fibroblast activation. We propose a stage-specific therapeutic framework for restoring adenosine balance in AS encompassing: (1) reconstitution of CD39/CD73 enzymatic activity, (2) receptor-selective modulation of A₂A and A₂B signaling pathways, and (3) exosome-mediated delivery of adenosine-regulating enzymes and microRNAs to reestablish immune homeostasis with cellular precision. The dual nature of adenosine-anti-inflammatory through A₂A receptor activation and pro-fibrotic via A₂B receptor engagement-necessitates context-aware targeting to suppress immune dysregulation without promoting ossification. This synthesis integrates molecular, cellular, and translational insights into a unified model of AS pathogenesis. By aligning mechanistic disruption with stage-specific and exosome-enabled interventions, it establishes a conceptual foundation for precision therapies aimed at recalibrating immune-stromal interactions and halting structural progression. This review synthesizes published mechanistic and translational evidence and includes hypothesis-generating therapeutic concepts that remain to be formally validated in AS.