1970s: Animal and tissue culture experiments provide evidence that osteoclast precursors reside in bone marrow, spleen, and peripheral blood ¹

1997: Publication identified osteoprotegerin (OPG) as a regulator of bone density. ² Independently, another group in Japan reported the identification of the identical molecule.³

1997: Researchers reported RANK cloned from a cDNA library of dendritic cells and found to be ubiquitously expressed in human tissue, with highest concentrations in skeletal muscle and the thymus; RANKL cloned ⁴

1998: Publication reported that severe osteoporosis caused by enhanced osteoclast formation and function is found in mice engineered to be OPG-deficient ^5,6

1998: Researchers published that OPG binding molecule identified and ligand cloned; ligand (OPGL) found to be identical to binding molecule (osteoclast differentiation factor [ODF]) and matched to RANK-L; OPG recognized as a decoy receptor ^7,8

1999: Article reports evidence that activated T cells regulate bone loss and joint destruction through OPG Ligand ⁹

2000: OPG/RANK/RANKL nomenclature standardized by American Society for Bone and Mineral Research

References

1. Aubin JE, Bonnelye E. Osteoprotegerin and its ligand: a new paradigm for regulation of osteoclastogenesis and bone resorption. Osteoporosis Intl. 2000;11:905-913. Review.
2. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoclast differentiation and activation. Cell. 1997;89:309-319.
3. Yasuda H, Shima N, Nakagawa N, et al. Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology. 1998;39:1329-1337.
4. Anderson DM, Maraskovsky E, Billingsley WL, et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 1997;390:175-179.
5. Mizuno A, Amizuka N, Irie K, et al. Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun. 1998;237:610-615.
6. Bucay N, Sarosi I, Dunstan CR, et al. Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998;12:1260-1268.
7. Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA. 1998;95:3597-3602.
8. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell . 1998;93:165-176.
9. Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397:315-323.