The study identifies a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor (OPG/OCIF) from mouse stromal cells, which is found to be identical to TRANCE/RANKL. This ligand, named osteoclast differentiation factor (ODF), is a member of the membrane-associated tumor necrosis factor ligand family and induces the formation of osteoclast-like cells (OCLs) from osteoclast progenitors. ODF mediates essential signals for osteoclast differentiation by interacting with OPG/OCIF, which inhibits osteoclastogenesis by interrupting this interaction. The expression of ODF is up-regulated by bone-resorbing factors in osteoblasts and stromal cells. Soluble ODF (sODF) can induce OCL formation from spleen cells in the absence of osteoblasts/stromal cells, and its effect is blocked by OPG/OCIF. ODF is also found to be expressed in various tissues, including trabecular bone, thymus, and lung. The study suggests that ODF, OPG/OCIF, and TRANCE/RANKL play crucial roles in both osteoclastogenesis and immune system regulation.The study identifies a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor (OPG/OCIF) from mouse stromal cells, which is found to be identical to TRANCE/RANKL. This ligand, named osteoclast differentiation factor (ODF), is a member of the membrane-associated tumor necrosis factor ligand family and induces the formation of osteoclast-like cells (OCLs) from osteoclast progenitors. ODF mediates essential signals for osteoclast differentiation by interacting with OPG/OCIF, which inhibits osteoclastogenesis by interrupting this interaction. The expression of ODF is up-regulated by bone-resorbing factors in osteoblasts and stromal cells. Soluble ODF (sODF) can induce OCL formation from spleen cells in the absence of osteoblasts/stromal cells, and its effect is blocked by OPG/OCIF. ODF is also found to be expressed in various tissues, including trabecular bone, thymus, and lung. The study suggests that ODF, OPG/OCIF, and TRANCE/RANKL play crucial roles in both osteoclastogenesis and immune system regulation.