SLC41A1-Mediated Magnesium Homeostasis Imbalance Promotes Osteoarthritis Progression by Inducing Abnormal Interaction Between Synovial Macrophages and Chondrocytes

Background: Osteoarthritis (OA) is a widespread degenerative joint disorder accompanied by marked M1/M2 macrophage imbalance in synovial tissue. The pathological interaction between synovial macrophages and impaired chondrocytes remains poorly defined. This study aims to determine whether SLC41A1-mediated magnesium homeostasis disturbance accelerates OA progression by triggering aberrant crosstalk between these two cell populations. Methods: A monoiodoacetate (MIA)-induced rat OA model was used to validate the in vivo cartilage-protective effect of intra-articular magnesium intervention, with cartilage integrity and synovial SLC41A1 expression, macrophage polarization evaluated by hematoxylin-eosin (HE), safranin O (S-O) staining and immunofluorescence. SLC41A1 expression in M1/M2 macrophages and magnesium’s regulatory effect on M1 were analyzed. After SLC41A1 knockdown, M2 phenotypic retention, magnesium homeostasis, mitochondrial function and chondrocyte degeneration markers in co-culture were further detected. Results: In the MIA-induced rat OA model, intra-articular magnesium injection significantly attenuated cartilage degeneration, reduced OARSI scores, suppressed chondrocyte apoptosis, upregulated Col2a1 and downregulated MMP13. Magnesium intervention also attenuated synovial hyperplasia, markedly downregulated aberrantly elevated SLC41A1 expression in the synovial/infrapatellar fat pad compartment and inhibited M1 pro-inflammatory macrophage polarization. In vitro, M1 macrophages exhibited lower intracellular magnesium and higher SLC41A1 expression than M2 macrophages, and this alteration was reversed by magnesium supplementation. SLC41A1 knockdown in macrophages attenuated their pro-oxidative, pro-apoptotic injury to co-cultured chondrocytes, restored mitochondrial function, preserved M2 anti-inflammatory phenotype and intracellular magnesium homeostasis in the IL-1β-activated co-culture system. Conclusions: SLC41A1 modulates macrophage magnesium homeostasis in the synovial/infrapatellar fat pad compartment, promotes pathological macrophage–chondrocyte crosstalk and OA progression, and serves as a potential magnesium-targeted OA intervention target.