Discovery and identification of Opgocif

In 1997, Simonet et al cloned a new member of the tumour necrosis factor (TNF) receptor family, termed osteoprotegerin (OPG). Interestingly, OPG lacked a transmembrane domain and represented a secreted TNF receptor (Fig. 2). Hepatic expression of Opg in transgenic mice resulted in osteopetrosis (Simonet et al 1997). Tsuda et al (1997) independently isolated a novel protein termed osteoclastogenesis inhibitory factor (OCIF) from conditioned media of human fibroblast culture. The cDNA sequence of OCIF is identical to that of OPG.

OPG/OCIF is a 401 amino acid protein with four cysteine-rich domains and two death domain homologous regions (Fig. 2). The death domain homologous regions share structural features with 'death domains' of TNF receptor p55, Fas and TRAIL receptors, which mediate apoptotic signals. OPG/OCIF strongly inhibited osteoclast formation induced by either 1a,25(OH)2D3, PTH, prostaglandin E2 (PGE2) or IL-11 in mouse co-culture (Simonet et al 1997, Tsuda et al 1997, Yasuda et al 1998a). Analyses of transgenic mice expressing Opg/Ocif and animals injected with OPG/OCIF have demonstrated that this factor suppresses osteoclastic bone resorption, resulting in increased bone mass (Simonet et al 1997, Yasuda et al 1998a). In contrast, Opg/Ocif knockout mice exhibited severe osteoporosis due to enhanced osteoclastogenesis (Bucay et al 1998, Mizuno et al 1998). These results suggest that OPG/OCIF is a physiologically important inhibitor of osteoclastic bone resorption.

® Hematopoietic stem ceil

i[j,Z5(OHjaD3

Osteoclast

□ OF: osteoclast different ¡at ion factor SOFA: slromal asteoclast forming activity TRAP: tartrate-™ si slant acid phosphatase CTR: calcitonin receptor

Osteoclast

□ OF: osteoclast different ¡at ion factor SOFA: slromal asteoclast forming activity TRAP: tartrate-™ si slant acid phosphatase CTR: calcitonin receptor

FIG. 1. A hypothetical concept of osteoclast differentiation. Osteotropic factors such as la,25 (OH)2D3, PTH and IL-11 stimulate osteoclast formation in co-cultures of osteoblasts/stromal cells and haematopoietic cells. Target cells for these factors are osteoblasts/stromal cells. Three different signalling pathways mediated by 1a,25(OH)2D3 receptor (vitamin D receptor), PTH/ PTHrP receptor, and gp130 similarly induce ODF (also called stromal osteoclast forming activity, SOFA) as a membrane associated factor in osteoblasts/stromal cells. Osteoclast progenitors of the monocyte—macrophage lineage recognize ODF bound to the cell membrane of osteoblasts/stromal cells through cell—cell interaction, then differentiate into osteoclasts which express TRAP and calcitonin receptors (CTR). M-CSF produced by osteoblasts/stromal cells is a prerequisite for both proliferation and differentiation of osteoclast progenitors.

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