Mechanism of bone destruction in RA. The intricate immune–bone interaction among lymphocytes, fibroblasts, osteoclasts and osteoblasts drives the bone destruction in RA. IL-17 produced by Th17 cells induces RANKL expression in synovial fibroblasts. Th17 cells induce the proinflammatory cytokines including TNF, IL-6 and IL-1, which further upregulate RANKL expression. Synovial fibroblasts in RA consist of two main types: inflammatory fibroblasts in the sublining layer and RANKL+ tissue-destructive fibroblasts in the lining layer. The polarization of tissue-destructive synovial fibroblasts is controlled by the transcriptional factor ETS1. The immunoglobulin immune complexes directly promote osteoclastogenesis. Desialylated immune complexes are particularly effective in this process, regulated by an IL-23–Th17 cell-dependent mechanism. TNF induces the production of Wnt inhibitors like DKK1 and sclerostin, suppressing bone formation