A novel molecular mechanism modulating osteoclast differentiation and function

Osteoclasts, the multinucleated giant cells that resorb bone, develop from hematopoietic cells of the monocyte/macrophage lineage. Osteoblasts, as wel l as bone marrow stromal cells, support osteoclast development through a me chanism of cell-to-cell interaction with osteoclast progenitors. We recentl y purified and molecularly cloned osteoclastogenesis inhibitory factor (OCI F), which was identical to osteoprotegerin (OPG). OPG/OCIF, a secreted memb er of the tumor necrosis factor (TNF) receptor family, inhibited differenti ation and activation of osteoclasts, A single class of high-affinity bindin g sites for OPG/OCIF appeared on a mouse bone marrow stromal cell line, ST2 , in response to 1 alpha,25-dihydroxyvitamin D3 [1,25(OH)(2)D-3] and dexame thasone (Dex), When the binding sites were occupied by OPG/OCIF, ST2 cells failed to support the osteoclast formation from spleen cells, To identify a n OPG/OCIF ligand, we screened a cDNA expression library of STZ cells treat ed with 1,25(OH)(2)D-3 and Dex using OPG/OCIF as a probe. The cloned molecu le was found to be a member of the membrane-associated TNF ligand family, a nd it induced osteoclast formation from mouse and human osteoclast progenit ors in the presence of macrophage colony-stimulating factor (M-CSF) in vitr o. Expression of its gene in osteoblasts/stromal cells was upregulated by o steotropic factors, such as 1,25(OH)(2)D-3, prostaglandin E-2 (PGE(2)), par athyroid hormone (PTH), and interleukin (IL)-11, A polyclonal antibody agai nst this protein, as well as OPG/OCIF, negated not only the osteoclastogene sis induced by the protein, but also bone resorption elicited by various os teotropic factors in a fetal mouse long bone culture system. These findings led us to conclude that the protein is osteoclast differentiation factor ( ODF), a long sought-after ligand that mediates an essential signal to osteo clast progenitors for their differentiation into active osteoclasts. Recent analyses of ODF receptor demonstrated that RANK, a member of the TNF recep tor family, is the signaling receptor for ODF in osteoclastogenesis, and th at OPG/OCIF acts as a decoy receptor for ODF to compete against RANK. The d iscovery of ODF, OPG/OCIF, and RANK opens a new era in the investigation of the regulation of osteoclast differentiation and function. (C) 1999 by Els evier Science Inc, All rights reserved.