Identity of Osteoclastogenesis Inhibitory Factor (OCIF) and Osteoprotegerin (OPG): A Mechanism by which OPG/OCIF Inhibits Osteoclastogenesisin Vitro¹

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.

A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis

“…19. Briefly, 10 6 spleen or bone marrow cells per ml were cultured in ␣-MEM supplemented with 10% FCS and 30 ng͞ml of both recombinant murine macrophage colony-stimulating factor (M-CSF) (R & D Systems) and recombinant human receptor activator of NF-B ligand (RANKL) (R & D Systems).…”

Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL

“…OCIF specifically inhibits in vitro OCL formation elicited through the three distinct signaling pathways stimulated by 1,25(OH) 2 D 3 , PTH, or IL-11 (8). The nucleotide sequence analysis of OCIF cDNA (9) has demonstrated that OCIF is identical to osteoprotegerin (OPG) (10), which was initially identified as a novel secreted member of the tumornecrosis factor (TNF) receptor family in an expressed sequence tag cDNA project (10). The analyses of transgenic mice overexpressing OPG͞OCIF and animals injected with OPG͞ OCIF have demonstrated that OPG͞OCIF suppresses bone resorption associated with osteoclast development (9,10).…”

“…The nucleotide sequence analysis of OCIF cDNA (9) has demonstrated that OCIF is identical to osteoprotegerin (OPG) (10), which was initially identified as a novel secreted member of the tumornecrosis factor (TNF) receptor family in an expressed sequence tag cDNA project (10). The analyses of transgenic mice overexpressing OPG͞OCIF and animals injected with OPG͞ OCIF have demonstrated that OPG͞OCIF suppresses bone resorption associated with osteoclast development (9,10). OPG͞OCIF lacks apparent transmembrane domain (9,10) and seems to act as a soluble inhibitory receptor in osteoclastogenesis.…”

“…The analyses of transgenic mice overexpressing OPG͞OCIF and animals injected with OPG͞ OCIF have demonstrated that OPG͞OCIF suppresses bone resorption associated with osteoclast development (9,10). OPG͞OCIF lacks apparent transmembrane domain (9,10) and seems to act as a soluble inhibitory receptor in osteoclastogenesis.…”

Evidence for a Role of a Tumor Necrosis Factor-α (TNF-α)-converting Enzyme-like Protease in Shedding of TRANCE, a TNF Family Member Involved in Osteoclastogenesis and Dendritic Cell Survival

“…TRANCE mediates its effects through the membrane-anchored TRANCE receptor (TRANCE-R, also referred to as RANK (receptor activator of nuclear factor-B)), which results in activation of c-Jun Nterminal kinase and nuclear factor-B (2,5). Finally TRANCE is known to bind to a soluble receptor, termed osteoprotegerin or osteoclast inhibitory factor (OPG/OCIF), which is a member of the TNF-␣ receptor family (6). OPG/OCIF presumably functions as a decoy receptor, since systemic overexpression or injection of OPG/OCIF causes osteopetrosis in mice (7), whereas OPG/OCIF deficiency results in osteoporosis (8).…”