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Discovery of the RANKL/RANK/OPG system

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A Correction to this article was published on 13 January 2021

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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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Change history

  • 13 January 2021

    In the original publication of the article, reference 12 was published incorrectly as follows.

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Acknowledgements

I thank all collaborators, especially Yoshiya Tomimori, Tetsuro Enomoto, and Yuriko Furuya, for their help in the preparation of the manuscript.

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  1. Nagahama Institute for Biochemical Science, Oriental Yeast Co., Ltd., 50, Kano-cho, Nagahama, Shiga, 526-0804, Japan

    Hisataka Yasuda

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Dr. Hisataka Yasuda is an employee of Oriental Yeast Co., Ltd.

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Yasuda, H. Discovery of the RANKL/RANK/OPG system. J Bone Miner Metab 39, 2–11 (2021). https://doi.org/10.1007/s00774-020-01175-1

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