Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone.

Nature Metabolism
Tatsuo AsanoHiroshi Takayanagi

Abstract

Receptor activator of NF-κB ligand (RANKL) is a multifunctional cytokine known to affect immune and skeletal systems, as well as oncogenesis and metastasis1-4. RANKL is synthesized as a membrane-bound molecule, and cleaved into its soluble form by proteases5-7. 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)5-7,9 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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Citations

Sep 15, 2019·Nature Reviews. Endocrinology·Claire Greenhill
Feb 13, 2020·Inflammation and Regeneration·Takehito OnoTomoki Nakashima
Apr 14, 2020·Proceedings of the Japan Academy. Series B, Physical and Biological Sciences·Hiroshi Takayanagi
Oct 14, 2020·Journal of Bone and Mineral Metabolism·Masashi HonmaHiroshi Suzuki
Oct 19, 2020·Journal of Bone and Mineral Metabolism·Masayuki Tsukasaki
Dec 9, 2020·Nature Metabolism·Masayuki TsukasakiHiroshi Takayanagi
Jan 3, 2021·Journal of Bone and Mineral Metabolism·Kazuo Okamoto
Jan 4, 2021·Journal of Bone and Mineral Metabolism·Hisataka Yasuda
Jan 14, 2021·Journal of Bone and Mineral Metabolism·Matthew C Walsh, Yongwon Choi
Feb 2, 2021·Frontiers in Immunology·Takeshi Nitta, Hiroshi Takayanagi
Apr 6, 2021·Current Osteoporosis Reports·Manish Adhikari, Jesús Delgado-Calle
Aug 28, 2021·Cells·Sandra CasimiroLuis Costa
Aug 3, 2021·Physiological Reviews·Jesus Delgado-Calle, Teresita Bellido

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Methods Mentioned

BETA
ELISA
flow cytometry
transfection
FACS

Software Mentioned

TRI
BON
FlowJo
WinROOF
Multi Gauge
IndiGO
Diva
3D
ImageQuant

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