Polydeoxyribonucleotide (PDRN) in Osteoarthritis: Immunomodulatory and Matrix-Supportive Potential, A2A Receptor-Associated Mechanisms, and Translational Challenges

Osteoarthritis (OA) is a multifactorial whole-joint disorder characterized by cartilage degeneration, synovial inflammation, subchondral bone remodeling, pain, and functional impairment. Polydeoxyribonucleotide (PDRN), a DNA-derived biological preparation commonly obtained from salmonid sperm, has been investigated as a potential adjunctive therapeutic candidate for OA because of its proposed anti-inflammatory, anti-apoptotic, angiogenesis-related, and tissue-protective properties. This review critically evaluates OA-specific evidence for PDRN, including cellular and mesenchymal stem cell models, intra-articular PDRN-containing interventions, and key translational limitations. In OA-related cellular models, PDRN has been associated with reduced inflammatory and catabolic mediator expression, restoration of aggrecan expression, and support for chondrogenic differentiation under inflammatory stress. However, these findings do not establish structural cartilage regeneration or disease modification in vivo. Limited clinical evidence suggests that PDRN-containing interventions, including hyaluronic acid (HA) plus PDRN, may improve pain and functional outcomes in knee OA; the independent contribution of PDRN in combination regimens and its long-term structural and safety effects remain uncertain. Evidence from ischemia/reperfusion models is discussed only as supporting mechanistic context for PDRN-associated modulation of inflammation and apoptosis. Future studies should standardize product characterization, establish A2A receptor dependency, evaluate safety after repeated intra-articular administration, and conduct adequately powered trials incorporating functional, imaging-based, structural, and safety outcomes.