IDENTITY OF OSTEOCLASTOGENESIS INHIBITORY FACTOR (OCIF) AND OSTEOPROTEGERIN (OPG) - A MECHANISM BY WHICH OPG OCIF INHIBITS OSTEOCLASTOGENESIS IN-VITRO/

The morphogenesis and remodeling of bone depends on the integrated act ivity of osteoblasts that form bone and osteoclasts that resorb bone. We previously reported the isolation of a new cytokine termed osteocla stogenesis inhibitory factor, OCIF, which specifically inhibits osteoc last development. Here we report the cloning of a complementary DNA of human OCIF. OCIF is identical to osteoprotegerin (OPG), a soluble mem ber of the tumor-necrosis factor receptor family that inhibits osteocl astogenesis. Recombinant human OPG/OCIF specifically acts on bone tiss ues and increases bone mineral density and bone volume associated with a decrease of active osteoclast number in normal rats. Osteoblasts or bone marrow-derived stromal cells support osteoclastogenesis through cell-to-cell interactions. A single class of high affinity binding sit es for OPG/OCIF appears on a mouse stromal cell line, ST2, in response to 1,25-dihydroxyvitamin D-3. An anti-OPG/OCIF antibody that blocks t he binding abolishes the biological activity of OPG/OCIF. When the sit es are blocked with OPG/OCIF, ST2 cells fail to support osteoclastogen esis. These results suggest that the sites are involved in cell-to-cel l signaling between stromal cells and osteoclast progenitors and that OPG/OCIF inhibits osteoclastogenesis by interrupting the signaling thr ough the sites.