RANKL, a necessary chance for clinical application to osteoporosis and cancer-related bone diseases

Figure 1 A model illustrating a mechanism by which osteoblasts/stromal cells regulate osteoclast differentiation and activation. Three distinct signals stimulated by 1,25(OH)₂D₃, PTH/PGE₂, and interleukin (IL)-11 induce receptor activator of nuclear factor-κB ligand (RANKL) expression on osteoblasts/stromal cells. RANKL mediates a signal for osteoclastogenesis through RANK produced on osteoclast progenitors. Osteoprotegerin (OPG) inhibits osteoclastogenesis by interrupting the binding of RANKL and RANK. Macrophage colony-stimulating factor (M-CSF) produced by osteoblasts/stromal cells is also indispensable for proliferation and differentiation of osteoclast progenitors. Soluble RANKL (sRANKL) is produced by digestion of RANKL with metalloproteinases and may regulate osteoclastogenesis.