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Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone

Nature Metabolism volume 1, pages 868–875 (2019)Cite this article

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Abstract

Receptor activator of NF-κB ligand (RANKL) is a multifunctional cytokine known to affect immune and skeletal systems, as well as oncogenesis and metastasis1,2,3,4. RANKL is synthesized as a membrane-bound molecule, and cleaved into its soluble form by proteases5,6,7. As the soluble form of RANKL does not contribute greatly to bone remodelling or ovariectomy-induced bone loss8, whether soluble RANKL has a role in pathological settings remains unclear. Here we show that soluble RANKL promotes the formation of tumour metastases in bone. Mice that selectively lack soluble RANKL (Tnfsf11ΔS/ΔS)5,6,7,9 have normal bone homoeostasis and develop a normal immune system but display markedly reduced numbers of bone metastases after intracardiac injection of RANK-expressing melanoma and breast cancer cells. Deletion of soluble RANKL does not affect osteoclast numbers in metastatic lesions or tumour metastasis to non-skeletal tissues. Therefore, soluble RANKL is dispensable for physiological regulation of bone and immune systems, but has a distinct and pivotal role in the promotion of bone metastases.

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Fig. 1: Tnfsf11ΔS/ΔS mice do not exhibit any discernible osteopetrotic phenotype.
Fig. 2: Soluble RANKL is dispensable for lymph node development and mTEC differentiation.
Fig. 3: Soluble RANKL promotes bone metastasis of B16F10 melanoma cells without affecting osteoclastogenesis.
Fig. 4: Contribution of soluble RANKL to bone metastasis of breast cancer cells.

Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank K. Miyazono, N. Komatsu, K. Kusubata, Y. Ogiwara, S. Nitta, K. Nagashima, M. Tsukasaki, M. Inoue, Y. Nakayama (The University of Tokyo), S. Sawa (Kyushu University), T. Nakashima (Tokyo Medical and Dental University) and M. Hattori (Tokyo Women’s Medical University) for thoughtful discussion and valuable technical assistance. This work was supported in part by a Practical Research Project for Rare/Intractable Diseases grant (JP17ek0109106) from the Japan Agency for Medical Research and Development; a Grant-in-Aid for Specially Promoted Research (15H05703), Young Scientists A (15H05653), Scientific Research B (16H05202 and 18H02919), Challenging Research (Pioneering) (17K19582) and the Japan Society for the Promotion of Science (JSPS) fellow (17J04280); Grants-in Aid for Research from the National Center for Global Health and Medicine (26-105 and 29-1001); The Japanese Society for Bone and Mineral Research Rising Stars Grant; and grants from Taiju Life Social Welfare Foundation, Astellas Research Support and Kobayashi Foundation for Cancer Research. T.A. was supported by a JSPS Research Fellowship for Young scientists.

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Authors and Affiliations

  1. Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan

    Tatsuo Asano, Yuta Nakai, Masanori Tsutsumi, Ryunosuke Muro, Ayako Suematsu, Kyoko Hashimoto, Takeshi Nitta & Hiroshi Takayanagi

  2. Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan

    Kazuo Okamoto

  3. Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan

    Tadashi Okamura

  4. Section of Animal Models, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan

    Tadashi Okamura

  5. Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Shogo Ehata

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Contributions

T.A. performed most of the experiments, interpreted the results and prepared the manuscript. K.O. designed the study, interpreted the results and contributed to the manuscript preparation. M.T. and T.N. contributed to analyses of the thymus. A.S. assisted with bone analyses. R.M. generated genetically modified cell lines. Y.N., K.H. and S.E. contributed to analysis of the bone metastasis. T.O. generated genetically modified mice. H.T. directed the project and wrote the manuscript.

Corresponding authors

Correspondence to Kazuo Okamoto or Hiroshi Takayanagi.

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Competing interests

The Department of Osteoimmunology is an endowment department, supported with an unrestricted grant from AYUMI Pharmaceutical Corporation, Chugai Pharmaceutical, MIKI HOUSE and Noevir.

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Peer review information: Primary Handling Editor: Pooja Jha.

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Asano, T., Okamoto, K., Nakai, Y. et al. Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone. Nat Metab 1, 868–875 (2019). https://doi.org/10.1038/s42255-019-0104-1

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