Plant-Derived Polyphenols in Osteoarthritis: Mechanisms, Delivery Systems, and Therapeutic Synergy

Osteoarthritis (OA) is a common, disabling joint disease characterized by complex inflammatory, oxidative, and catabolic cascades that culminate in progressive cartilage degradation, subchondral bone remodeling, and synovitis. Standard pharmacological treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs) provide symptomatic relief of pain but do not prevent the progression of the disease and are often associated with serious gastrointestinal, renal and cardiovascular side effects following long-term use. Epigallocatechin-3-gallate (EGCG), resveratrol, curcumin, quercetin, luteolin and genistein are naturally occurring polyphenols which have been identified as promising disease-modifying osteoarthritis drugs (DMOADs). Mechanistically, these phytochemicals suppress key pro-inflammatory signaling pathways (NF-κB, MAPK), downregulate matrix-degrading enzymes (MMP-13, ADAMTS-5), mitigate reactive oxygen species (ROS), and attenuate chondrocyte apoptosis and senescence. Polyphenols have been shown in pre-clinical and clinical trials to reduce joint pain and preserve cartilage integrity. They also have a synergistic effect with conventional drugs, resulting in lower doses and reduced toxicity. However, their clinical translation has been hampered by poor oral bioavailability, rapid Phase II metabolism, and short intra-articular retention. Advanced drug-delivery systems, such as nanoparticles, liposomes, and sustained-release hydrogels, are essential to overcome these pharmacokinetic bottlenecks and realize their full therapeutic potential in OA management.