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This article is part of the supplement: Proceedings of the 8th Global Arthritis Research Network (GARN) Meeting and 1st Bio-Rheumatology International Congress (BRIC)

Oral presentation

From discovery of RANKL to clinical application of anti-human RANKL antibody

Hisataka Yasuda1*, Yuriko Furuya2 and Kohji Uchida2

  • * Corresponding author: Hisataka Yasuda

Author Affiliations

1 Bioindustry Division, Oriental Yeast Co Ltd, Tokyo, Japan

2 Nagahama Institute for Biochemical Science, Oriental Yeast Co Ltd, Shiga, Japan

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Arthritis Research & Therapy 2012, 14(Suppl 1):O33  doi:10.1186/ar3588

The electronic version of this article is the complete one and can be found online at: http://arthritis-research.com/content/14/S1/O33


Published:9 February 2012

© 2012 Yasuda et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Oral presentation

Osteoporosis is a common bone disease characterized by reduced bone and increased risk of fracture. In postmenopausal women osteoporosis results from bone loss attributable to estrogen deficiency. Receptor activator of nuclear factor-B ligand (RANKL) is a pivotal osteoclast differentiation factor [1]. Discovery of RANKL has opened a new era in the understanding of mechanisms in osteoclast differentiation over the last decade. The discovery also results in the development of a fully human anti-RANKL neutralizing monoclonal antibody (called denosumab) and denosumab has been approved for the treatment of osteoporosis in Europe and the US.

Here I report a novel rapid bone loss model with GST-RANKL as the first topic [2]. Pharmacologic studies of candidates for the treatment of osteoporosis with this model can be done in short periods such as 3 days and a couple of weeks although it took several months in the conventional methods with ovariectomized(OVX)-rats. This model also is useful for the rapid analyses in the functions of osteoclasts in vivo. The RANKL-induced bone loss model is the simplest, fastest, and easiest of all osteoporosis models and could be a gold standard in the evaluation of novel drug candidates for osteoporosis as well as OVX.

Osteopetrosis is generally caused by failure of osteoclast-mediated resorption of skeleton. There are a numerous mouse models of osteopetrosis without osteoclasts, including c-fos deficient mice, op/op mice, RANKL-deficient mice and RANK-deficient mice. As the second topic I report a mouse model of osteopetrosis induced by a denosumab-like anti-mouse neutralizing monoclonal RANKL antibody [3]. One injection of the antibody increased bone mass markedly with remarkable decrease in osteoclast surface and number after two weeks. In addition, osteoblast surface, mineral apposition rate, and bone formation rate were also reduced markedly. These results are consistent with the recent report treating human RANKL-knock in mice with denosumab [4]. These inducible models of osteoporosis and osteopetrosis using normal mice exhibit exactly mirror images in terms of change in bone mass and are quite useful to accelerate research on osteoclast biology as well as bone metabolism in vivo.

In conclusion, the discovery of OPG/RANKL/RANK system guided us to reveal the mechanism regulating osteoclast differentiation and activation. The past decade has witnessed significant progress in the development of the RANKL antibody as a pharmaceutical agent. This is a story from a discovery of RANKL to clinical application of anti-human RANKL antibody.

References

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    Proc Natl Acad Sci USA 1998, 95:3597-3602. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

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  3. Furuya Y, Mori K, Ninomiya T, et al.: Increased bone mass in mice after a single injection of an anti-RANKL neutralizing antibody: evidence for a bone anabolic effect of PTH in mice with few osteoclasts.

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