Osteoclast formation in the joint. Monocytic cells in the synovium serve as osteoclast precursors. Upon exposure to macrophage colony-stimulating factor (MCSF) and RANKL synthesized by T cells and synovial fibroblasts, osteoclasts fuse to polykaryons termed preosteoclasts, which then undergo further differentiation into mature osteoclasts, acquiring specific features such as the ruffled membrane. Inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin (IL)-1, IL-6, and IL-17 increase the expression of RANKL and thus support osteoclastogenesis in the joint. In contrast, regulatory T (Treg) cells block osteoclast formation via CTLA4. RANKL, receptor activator of nuclear factor-kappa B ligand.