title: Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL.
abstract: Osteoclasts, the multinucleated cells that resorb bone, develop from hematopoietic cells of monocyte/macrophage lineage. Osteoclast-like cells (OCLs) are formed by coculturing spleen cells with osteoblasts or bone marrow stromal cells in the presence of bone-resorbing factors. The cell-to-cell interaction between osteoblasts/stromal cells and osteoclast progenitors is essential for OCL formation. Recently, we purified and molecularly cloned osteoclastogenesis-inhibitory factor (OCIF), which was identical to osteoprotegerin (OPG). OPG/OCIF is a secreted member of the tumor necrosis factor receptor family and inhibits osteoclastogenesis by interrupting the cell-to-cell interaction. Here we report the expression cloning of a ligand for OPG/OCIF from a complementary DNA library of mouse stromal cells. The protein was found to be a member of the membrane-associated tumor necrosis factor ligand family and induced OCL formation from osteoclast progenitors. A genetically engineered soluble form containing the extracellular domain of the protein induced OCL formation from spleen cells in the absence of osteoblasts/stromal cells. OPG/OCIF abolished the OCL formation induced by the protein. Expression of its gene in osteoblasts/stromal cells was up-regulated by bone-resorbing factors. We conclude that the membrane-bound protein is osteoclast differentiation factor (ODF), a long-sought ligand mediating an essential signal to osteoclast progenitors for their differentiation into osteoclasts. ODF was found to be identical to TRANCE/RANKL, which enhances T-cell growth and dendritic-cell function. ODF seems to be an important regulator in not only osteoclastogenesis but also immune system.
authors.affiliation: Research Institute of Life Science, Snow Brand Milk Products Co., Ltd., 519 Ishibashi-machi, Shimotsuga-gun, Tochigi 329-0512, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yasuda
authors.forename: N
authors.initials: N
authors.lastname: Shima
authors.forename: N
authors.initials: N
authors.lastname: Nakagawa
authors.forename: K
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: M
authors.initials: M
authors.lastname: Kinosaki
authors.forename: S
authors.initials: S
authors.lastname: Mochizuki
authors.forename: A
authors.initials: A
authors.lastname: Tomoyasu
authors.forename: K
authors.initials: K
authors.lastname: Yano
authors.forename: M
authors.initials: M
authors.lastname: Goto
authors.forename: A
authors.initials: A
authors.lastname: Murakami
authors.forename: E
authors.initials: E
authors.lastname: Tsuda
authors.forename: T
authors.initials: T
authors.lastname: Morinaga
authors.forename: K
authors.initials: K
authors.lastname: Higashio
authors.forename: N
authors.initials: N
authors.lastname: Udagawa
authors.forename: N
authors.initials: N
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Suda
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002352:Carrier Proteins; D002450:Cell Communication / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics* / Q000302:isolation & purification; D006023:Glycoproteins / Q000819:agonists* / Q000494:pharmacology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D010010:Osteoclasts / Q000166:cytology*; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D017154:Stromal Cells / Q000166:cytology*
chemical_list: D002352:Carrier Proteins; D018076:DNA, Complementary; D006023:Glycoproteins; D008024:Ligands; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse