Purinergic signaling in osteoarthritis: Mechanistic insights into pathogenesis and therapeutic targeting

Osteoarthritis (OA) is a degenerative joint disease driven by a complex interplay of inflammation, extracellular matrix degradation, subchondral bone remodeling, and chronic pain. Purinergic signaling has emerged as a key regulator of OA pathogenesis, where dysregulated extracellular nucleotide-mediated P2 receptor activation and impaired adenosine-mediated P1 receptor signaling disrupt joint homeostasis. Excessive activation of P2X and P2Y receptors amplifies inflammatory cascades, promotes chondrocyte apoptosis, enhances matrix metalloproteinase activity, and sensitizes nociceptive pathways, while reduced P1 receptor signaling, particularly via A2A and A3, compromises anti-inflammatory and chondroprotective mechanisms. Additionally, disruptions in extracellular nucleotide metabolism exacerbate disease progression by perpetuating synovial fibrosis, cartilage destruction, and persistent pain. This review provides a mechanistic overview of purinergic receptor dysregulation in OA, detailing its roles in synovial inflammation, cartilage homeostasis, subchondral bone remodeling, and pain transmission. Furthermore, this review explores emerging therapeutic strategies targeting purinergic receptors, particularly P2 receptor antagonists and P1 receptor agonists, which are being developed as selective ligands to restore joint homeostasis and attenuate disease progression. Understanding the intricate molecular crosstalk between the P2 and P1 receptor pathways will be critical for the development of precision therapies aimed at modifying OA pathophysiology and improving clinical outcomes.