Figure 3.

Osteoclast formation. There is a balance between bone-forming and bone-resorbing activities in normal conditions. The bone-resorbing cells’ osteoclasts form through the fusion of preosteoclasts, which are derived from monocytes/macrophages and/or osteoclast-biased hematopoietic stem cells (HSC). Osteoblasts and stromal cells in the bone produce a receptor activator of nuclear factor-kappa-Β ligand (RANKL), which belongs to a tumor necrosis factor family of proteins. RANKL binds to its receptor RANK expressed on the surface of preosteoclasts and osteoclasts, promoting fusion and formation of syncytial multinuclear osteoclasts. After further activation by various cytokines, mature osteoclasts acquire a bone-resorbing activity. Osteoblast and stromal cells also produce osteoprotegerin (OPC) that prevents excessive bone resorption by binding to and depleting RANKL. Thus, RANKL/OPC ratio determines bone resorption or bone formation.