Discovery of the RANKL/RANK/OPG System

Overview

Journal J Bone Miner Metab

Specialty Endocrinology

Date 2021 Jan 3

PMID 33389131

Citations 79

Authors

Hisataka Yasuda

Affiliations

Soon will be listed here.

Abstract

Almost a quarter century has passed since discovery of receptor activator of NF-κB ligand (RANKL). This discovery had a major impact on identification of mechanisms regulating osteoclast differentiation and function, establishment of a research field bridging bone and the immune system (osteoimmunology), and development of a fully human anti-RANKL neutralizing antibody (denosumab). Denosumab is now clinically available for treatment of osteoporosis and cancer-induced bone diseases in the US, Europe and many other countries, including Japan. Denosumab is a so-called blockbuster drug, with sales of 5.0 billion US dollars in 2019. This is a real success story from bench to bedside. In this review, the pivotal roles of the RANKL/RANK/OPG system in osteoclast differentiation and function are shown. RANKL is a ligand required for osteoclast generation, RANK is the receptor for RANKL, and osteoprotegerin (OPG) is a decoy receptor for RANKL. The review covers recent results showing the importance of RANKL on osteoblasts in regulation of osteogenesis and the role of RANKL-RANK dual signaling in coupling of bone resorption and formation, including demonstration of RANKL reverse signaling that we had previously hypothesized. Possible applications of anti-RANKL antibody in treatment of cancer are also discussed.

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References

Rodan G, Martin T . Role of osteoblasts in hormonal control of bone resorption--a hypothesis. Calcif Tissue Int. 1981; 33(4):349-51. DOI: 10.1007/BF02409454. View

Suda T, Takahashi N, Martin T . Modulation of osteoclast differentiation. Endocr Rev. 1992; 13(1):66-80. DOI: 10.1210/edrv-13-1-66. View

Takahashi N, Akatsu T, Udagawa N, Sasaki T, Yamaguchi A, Moseley J . Osteoblastic cells are involved in osteoclast formation. Endocrinology. 1988; 123(5):2600-2. DOI: 10.1210/endo-123-5-2600. View

Takahashi N, Udagawa N, Akatsu T, Tanaka H, Isogai Y, Suda T . Deficiency of osteoclasts in osteopetrotic mice is due to a defect in the local microenvironment provided by osteoblastic cells. Endocrinology. 1991; 128(4):1792-6. DOI: 10.1210/endo-128-4-1792. View

Tsuda E, Goto M, Mochizuki S, Yano K, Kobayashi F, Morinaga T . Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochem Biophys Res Commun. 1997; 234(1):137-42. DOI: 10.1006/bbrc.1997.6603. View

Higashio K, Shima N, Goto M, ITAGAKI Y, Nagao M, Yasuda H . Identity of a tumor cytotoxic factor from human fibroblasts and hepatocyte growth factor. Biochem Biophys Res Commun. 1990; 170(1):397-404. DOI: 10.1016/0006-291x(90)91287-3. View

Yasuda H, Shima N, Nakagawa N, Mochizuki S, Yano K, Fujise N . Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology. 1998; 139(3):1329-37. DOI: 10.1210/endo.139.3.5837. View

Simonet W, Lacey D, Dunstan C, Kelley M, Chang M, Luthy R . Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997; 89(2):309-19. DOI: 10.1016/s0092-8674(00)80209-3. View

Bucay N, Sarosi I, Dunstan C, Morony S, Tarpley J, Capparelli C . osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998; 12(9):1260-8. PMC: 316769. DOI: 10.1101/gad.12.9.1260. View

10.

Mizuno A, Amizuka N, Irie K, Murakami A, Fujise N, Kanno T . Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun. 1998; 247(3):610-5. DOI: 10.1006/bbrc.1998.8697. View

11.

Udagawa N, Takahashi N, Akatsu T, Sasaki T, Yamaguchi A, Kodama H . The bone marrow-derived stromal cell lines MC3T3-G2/PA6 and ST2 support osteoclast-like cell differentiation in cocultures with mouse spleen cells. Endocrinology. 1989; 125(4):1805-13. DOI: 10.1210/endo-125-4-1805. View

12.

Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S . Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A. 1998; 95(7):3597-602. PMC: 19881. DOI: 10.1073/pnas.95.7.3597. View

13.

Lacey D, Timms E, Tan H, Kelley M, Dunstan C, Burgess T . Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998; 93(2):165-76. DOI: 10.1016/s0092-8674(00)81569-x. View

14.

Anderson D, Maraskovsky E, Billingsley W, Dougall W, Tometsko M, Roux E . A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature. 1997; 390(6656):175-9. DOI: 10.1038/36593. View

15.

Wong B, Rho J, Arron J, Robinson E, Orlinick J, Chao M . TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem. 1997; 272(40):25190-4. DOI: 10.1074/jbc.272.40.25190. View

16.

Kong Y, Yoshida H, Sarosi I, Tan H, Timms E, Capparelli C . OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999; 397(6717):315-23. DOI: 10.1038/16852. View

17.

Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Yano K . RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun. 1999; 253(2):395-400. DOI: 10.1006/bbrc.1998.9788. View

18.

Hsu H, Lacey D, Dunstan C, Solovyev I, Colombero A, Timms E . Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc Natl Acad Sci U S A. 1999; 96(7):3540-5. PMC: 22329. DOI: 10.1073/pnas.96.7.3540. View

19.

Dougall W, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T . RANK is essential for osteoclast and lymph node development. Genes Dev. 1999; 13(18):2412-24. PMC: 317030. DOI: 10.1101/gad.13.18.2412. View

20.

Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng J . Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med. 2011; 17(10):1231-4. DOI: 10.1038/nm.2452. View