Osteoprotegerin (OPG) has recently been identified as a new member of the tumor necrosis factor (TNF)-receptor (TNF-R) superfamily (1–3). It is a glycoprotein with seven structural domains, including four TNF-R motifs at the N-terminus (domains 1–4), two death domain homologous regions (domains 5 and 6) which mediate cytotoxicity, and a C-terminus (domain 7) which contains a cysteine residue for homodimer formation (4). In contrast with other known members of the TNF-R superfamily, OPG (or osteoclastogenesis inhibitory factor, OCIF) lacks transmembrane domains, suggesting that it acts as a secreted cytokine receptor (1–4). Enthusiasm for this new cytokine receptor emerged from basic scientists and clinicians alike after it was shown that, by suppressing osteoclastogenesis, OPG is a potent inhibitor of bone resorption (1, 2, 5, 6). Moreover, overexpression of OPG in transgenic mice resulted in osteopetrosis (generalized increase in bone mass)(1) and prevented bone loss following ovariectomy (1, 2). The potent antiresorptive effects of OPG nurtured the hope that deciphering its mode of action would provide detailed insights into osteoclastogenesis, an integral part of the pathogenesis of metabolic bone diseases. However, while the effect of OPG was impressive and comparable with the most potent class of antiresorptive drugs, the bisphosphonates, the cognate ligand for OPG had remained unidentified, rendering OPG another orphan receptor and leaving a major piece of the puzzle of osteoclastogenesis missing. One year later, the cognate ligand for OPG (OPGL) has been identified independently by two groups (7, 8). After screening of OPG-binding cell surface proteins with an OPG immunoprobe, OPGL was expression-cloned and the human OPGL cDNA was isolated from lymph node (7) and stromal cell (8) cDNA libraries. Human OPGL (or osteoclast differentiation factor, ODF) consists of 317 amino acids and belongs to the class of type II transmembrane proteins (7, 8). OPGL exists in a cellbound and a soluble C-terminal form, both of which are bound by OPG (7). It is highly expressed in lymphoid tissues (lymph node, thymus, spleen) and trabecular bone, and to a lesser extent in bone marrow as well as in some bone marrow stromal and osteosarcoma cell lines (7, 8). OPGL mRNA expression in the murine marrow stromal cell line, ST2, is upregulated by vitamin D.

Furthermore, vitamin D, interleukin-11, prostaglandin E2 and parathyroid hormone increased OPGL mRNA expression in primary mouse osteoblasts (8). Within fetal bone, OPGL is mainly expressed in the cartilaginous anlagen and in hypertrophic chondrocytes, while in adult bone its expression is most abundant in the growth plate and the metaphysis, all of which are areas of active bone remodeling during growth (7). OPGL binds to the cell surface of osteoclastic lineage cells, and, in the presence of the permissive factor colony-stimuating factor-1 (CSF-1), it induces osteoclastogenesis in vitro in the absence of stromal cells, glucocorticoids and vitamin D, factors previously considered essential for osteoclastogenesis (7, 8). Importantly, OPGL stimulated bone resorption both in vitro (7, 8) and in vivo (7). The latter (after subcutaneous injection of recombinant OPGL into normal mice) was associated with an increased size and nuclearity of osteoclasts, massive bone loss and profound rapid-onset hypercalcemia (7). These studies unequivocally establish OPGL and OPG as a cybernetic couple that regulates bone mass by modulating osteoclastogenesis. OPGL appears to be the endogenous ‘master’cytokine, which is the conditio sine qua non for normal osteoclast differentiation and …