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The therapeutic mechanisms of methotrexate in RA include: inhibition of dihydrofolate reductase to reduce nucleic acid production and promote cell death (78), downregulation of Th1 cells and upregulation of Th2 cells and Tregs (79), amelioration of bone destruction by increasing osteoprotegerin (OPG) and decreasing RANKL (80), suppression of osteoclast differentiation (92), and inhibition of MMP expression and cartilage matrix absorption (93)