RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis

Osteoclast differentiation factor (ODF) is a ligand for osteoclastogenesis- inhibitory factor/osteoprotegerin (OCIF/OPG), and mediates an essential sig nal for osteoclastogenesis. Soluble-form ODF binds directly to osteoclast p rogenitors, suggesting the presence of a membrane-bound receptor for ODF (O DFR) on the cells. To understand the ODF-mediated signal transduction mecha nism in osteoclastogenesis, we molecularly cloned ODFR from a mouse macroph age-like osteoclast progenitor cell line, C7. Nucleotide sequence analysis revealed that ODFR is identical to RANK, a recently identified member of th e tumor necrosis factor receptor (TNFR) family, which is involved in the re gulation of dendritic cell function, A polyclonal antibody against the extr acellular domain of RANK induced osteoclastogenesis in the presence of macr ophage colony-stimulating factor (M-CSF). In contrast; both a genetically e ngineered soluble RANK and Fab fragment of the antibody blocked the binding of ODF to RANK and ODF-mediated osteoclastogenesis. These results indicate that RANK is the signaling receptor essential for ODF-mediated osteoclasto genesis. (C) 1998 Academic Press.