Plant Phenolic Compounds in Rheumatic and Musculoskeletal Diseases: Molecular Mechanisms, Clinical Evidence and Translational Challenges

Plant phenolic compounds have been investigated in rheumatic and musculoskeletal disorders because several of their biological activities involve inflammatory signaling, oxidative responses and tissue remodeling. This critical narrative review examines phenolic acids, flavonoids (including isoflavones), curcuminoids and stilbenes in osteoarthritis (OA), rheumatoid arthritis (RA) and osteoporosis. Terpenoids and alkaloids are also considered as chemically distinct plant-derived compounds of potential physiological relevance. Experimental studies report effects on NF-κB, MAPK and Nrf2 signaling, matrix metalloproteinases, ADAMTS enzymes and regulators of bone remodeling, including the RANKL/OPG axis. However, the clinical implications depend on the experimental model, compound exposure and disease indication. Randomized trials of certain curcumin formulations suggest short-term symptomatic improvements in knee OA, although the evidence is limited by variation in products and study quality. Human evidence for quercetin in RA remains limited, while clinical data do not establish disease-modifying effects of resveratrol or epigallocatechin-3-gallate. Genistein has been associated with changes in bone mineral density, but fracture prevention has not been demonstrated. Absorption, metabolism, tissue distribution, preparation-dependent toxicity and the lack of long-term clinical outcomes complicate translation. The review evaluates these limitations and identifies methodological requirements for future mechanistic and clinical studies of plant phenolics.