Intra-articular metformin and chlorogenic acid synergistically protect against cartilage degeneration by suppressing NF-κB/NLRP3 inflammasome axis in osteoarthritis
Abstract
Osteoarthritis (OA) is a leading cause of disability, driven by cartilage degradation, subchondral bone remodeling, and synovial inflammation. Activation of the NF-κB/NLRP3 inflammasome axis contributes to disease progression. This study investigated the chondroprotective and anti-inflammatory effects of intra-articular (IA) metformin (MET) and chlorogenic acid (CGA), alone or in combination, in a rabbit model of OA. OA was induced by monosodium iodoacetate (MIA) injection into the knee joints of male rabbits The rabbits were randomized into six groups: Control, MET + CGA, OA, OA + MET, OA + CGA, and OA + MET + CGA. Disease severity was evaluated via radiography, gross morphology, histopathology, and hematological and synovial fluid analyses. MIA induced OA manifested by joint space narrowing, osteophyte formation, and cartilage erosion, accompanied by elevated serum CRP, increased synovial IL-1β, IL-6, and TNF-α, and upregulation of NF-κB, NLRP3, caspase-1, GSDMD, IRF-1, and cartilage-degrading enzymes. MET or CGA alone significantly attenuated these changes, improving joint architecture, lowering inflammatory cytokines, and suppressing pyroptotic signaling. Combination therapy produced the most pronounced benefits, restoring near-normal cartilage structure, normalizing leukocyte profiles, and reducing molecular markers toward baseline. In silico findings revealed the affinity of CGA to bind with NLRP3 PYD, ASC PYD, IRF-1 and NF-κB p65. In conclusion, IA MET + CGA…
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