Abstract / Summary
Osteoarthritis (OA) is the most prevalent degenerative joint disease worldwide. OA involves chronic pain, subchondral bone remodeling, synovial inflammation, and progressive cartilage degeneration. Gut microbiota (GM) dysbiosis disturbs metabolic processes and systemic inflammation and induces joint deterioration through the gut-joint axis. Conventional pharmacological interventions are associated with adverse effects upon long-term use and merely alleviate symptoms but do not prevent the disease progression. Nutraceuticals are alternative for the treatment of OA due to their safety, multimodal activity, and potential disease-modifying properties. Among them, amino sugar derivatives such as glucosamine sulfate (GS) and chondroitin sulfate (CS) naturally occur in cartilage extracellular matrix and exhibit a range of biological actions. GS and CS exert their action by decreasing catabolic enzymes (MMPs, ADAMTS), suppressing pro-inflammatory signaling pathways (NF-κB, MAPK), stimulating anabolic processes (type II collagen and aggrecan synthesis), controlling oxidative stress, and blocking chondrocyte apoptosis. This review, in addition to future works, presents in-vitro, in-vivo, and clinical investigations to critically evaluate the molecular activities of CS and GS in the regulation of cartilage-related and inflammatory pathways in knee OA. We also emphasize their interactions with the GM, their synergistic potential, and the application of nanotechnology strategies to enhance therapeutic efficacy and bioavailability in OA. • Osteoarthritis is a systemic disorder driven by inflammation, oxidative stress, and dysregulated chondrocyte metabolism, with emerging roles for the gut-joint axis. • Glucosamine sulfate and chondroitin sulfate exert chondroprotective effects through anabolic stimulation, NF-κB inhibition, and suppression of MMP-13 and ADAMTS-5. • The efficacy of CS and GS is modulated by gut microbiota, with chondroitin sulfate enriching beneficial taxa such as Akkermansia muciniphila. • Conventional oral delivery of amino sugars is limited by low bioavailability and variable patient response due to microbial metabolism. • Nanotechnology-based delivery systems—including chitosan nanoparticles, liposomes, and gold nanoparticles—enhance targeting, retention, and controlled release in joint tissues. • Integrated strategies combining nutraceuticals, nanocarriers, and microbiome modulation represent a promising disease-modifying approach for osteoarthritis.