Pro-inflammatory cytokines, including TNF-α, IFN-γ, IL-1β, IL-6, and IL-17A, induce the production of MMP-1, MMP-3, MMP-9, MMP-13, phospholipase A2, and cyclooxygenase-2, which induce FLS to produce VEGF, IL-8, and RANKL, and promote the differentiation of monocytes into osteoclasts, all of which mediate bone destruction in RA (186, 187). This evidence concerns the gene PLA2G4A and rheumatoid arthritis.