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

## TL;DR

This paper proposes a new framework for treating axial spondyloarthritis by restoring adenosine balance to control inflammation and prevent bone damage.

## Contribution

A stage-specific therapeutic framework for restoring adenosine balance in axial spondyloarthritis using CD39/CD73 reconstitution, A2A/A2B signaling modulation, and exosome-based delivery.

## Key findings

- Adenosine depletion in axial spondyloarthritis impairs regulatory T cells and promotes Th17-driven inflammation.
- Restoring CD39/CD73 activity and modulating A2A/A2B receptors could rebalance immune and structural responses.
- Exosome-mediated delivery of enzymes and microRNAs offers a precise method to reestablish immune homeostasis.

## Abstract

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.