The immune system regulates bone resorption through enhanced osteoclastogenesis. Cells of the adaptive and innate immune systems contribute to regulation of bone turnover through production of cytokines and direct cell-cell interactions. Proinflammatory cytokines such as IL-6, IL-1β, and TNF-α are secreted by macrophages and fibroblasts secrete IL-6. Th17 lymphocytes produce IL-17, IL-6, and TNF-α. In RA these cytokines drive bone erosion by induction of RANKL expression by osteoblast stromal cells. Th17 lymphocytes also secrete RANKL, which binds to RANK receptor on osteoclast precursors triggering osteoclast maturation and activation, thus enhancing bone loss. Osteoprotegerin (OPG) is a soluble decoy receptor that inhibits RANKL binding to RANK thus limiting bone resorption. IL-17 increases RANKL expression and concomitantly decreases OPG expression in osteoblasts, causing enhanced formation of osteoclasts and bone erosion. Neutrophils also contribute to bone and cartilage degradation by secretion of degradative factors. IL, interleukin; RANK, receptor activator of NF-κB; Th, T-helper; TNF, tumor necrosis factor.