Identity of Osteoclastogenesis Inhibitory Factor (OCIF) and Osteoprotegerin (OPG): A Mechanism by which OPG/OCIF Inhibits Osteoclastogenesis<i>in Vitro</i>¹

TLDR

Bone remodeling depends on the coordinated activity of osteoblasts and osteoclasts, with osteoblasts or bone‑marrow stromal cells supporting osteoclastogenesis, and a newly isolated cytokine, OCIF, that specifically inhibits osteoclast development. The study reports the cloning of a complementary DNA encoding human OCIF. OCIF is identical to osteoprotegerin, a soluble TNF‑receptor family member that inhibits osteoclastogenesis; recombinant OPG/OCIF increases bone mineral density and volume while reducing active osteoclasts in rats, and its activity requires high‑affinity binding sites on stromal cells that mediate cell‑to‑cell signaling with osteoclast progenitors.

Abstract

The morphogenesis and remodeling of bone depends on the integrated activity of osteoblasts that form bone and osteoclasts that resorb bone. We previously reported the isolation of a new cytokine termed osteoclastogenesis inhibitory factor, OCIF, which specifically inhibits osteoclast development. Here we report the cloning of a complementary DNA of human OCIF. OCIF is identical to osteoprotegerin (OPG), a soluble member of the tumor-necrosis factor receptor family that inhibits osteoclastogenesis. Recombinant human OPG/OCIF specifically acts on bone tissues 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 sites for OPG/OCIF appears on a mouse stromal cell line, ST2, in response to 1,25-dihydroxyvitamin D3. An anti-OPG/OCIF antibody that blocks the binding abolishes the biological activity of OPG/OCIF. When the sites are blocked with OPG/OCIF, ST2 cells fail to support osteoclastogenesis. These results suggest that the sites are involved in cell-to-cell signaling between stromal cells and osteoclast progenitors and that OPG/OCIF inhibits osteoclastogenesis by interrupting the signaling through the sites.