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Modification of the RANKL-RANK-binding site for the immunotherapeutic treatment of osteoporosis

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Abstract

Summary

Here, we proposed the use of mutated RANKL as an immunogen for active immunization and to induce anti-cytokine antibodies for osteoporosis treatment.

Introduction

Osteoclasts are responsible for bone resorption in bone-related disorders. Anti-cytokine therapeutic antibodies such as denosumab are effective for the treatment of osteoporosis. However, problems with antibody manufacturing and the immunogenicity caused by multiple antibody doses have led to the use of auto-cytokines as immunogens to induce anti-cytokine antibodies.

Methods

RANKL was point-mutated based on the crystal structure of the complex of RANKL and its receptor RANK.

Results

As a proof of concept, immunization with RANKL produced high levels of specific antibodies and blocked osteoclast development in vitro and inhibited osteoporosis in RANKL-treated or ovariectomized mouse models.

Conclusions

The results demonstrate the successful use of mutated RANKL as an immunogen for the induction of anti-RANKL immune response. This strategy is useful in general anti-cytokine immunotherapy to avoid toxic side effects of osteoporosis treatment.

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Funding source

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education (2018R1D1A1B07047024, 2017R1D1A3B03031764).

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Author notes

  1. Y. Ko and G. Lee contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopaedic Surgery, Chosun University Hospital, Gwangju, 61453, South Korea

    Y. Ko, G. Lee, B. Kim, M. Park, Y. Jang & W. Lim

  2. Laboratory of Orthopaedic Research, Chosun University Hospital, Gwangju, 61453, South Korea

    Y. Ko, G. Lee, B. Kim, M. Park, Y. Jang & W. Lim

  3. Department of Premedical Program, School of Medicine, Chosun University, Gwangju, 61452, South Korea

    Y. Jang & W. Lim

Authors
  1. Y. Ko
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  2. G. Lee
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  3. B. Kim
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  4. M. Park
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  5. Y. Jang
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  6. W. Lim
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Contributions

YK, GL, BK, MP, YJ, and WL performed the experiments. YK and GL reviewed, analyzed, and interpreted the data. YK, GL, and WL wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to W. Lim.

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The authors declare that they have no conflicts of interest.

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Ko, Y., Lee, G., Kim, B. et al. Modification of the RANKL-RANK-binding site for the immunotherapeutic treatment of osteoporosis. Osteoporos Int 31, 983–993 (2020). https://doi.org/10.1007/s00198-019-05200-6

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  • DOI: https://doi.org/10.1007/s00198-019-05200-6

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