Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone

Autor: Shogo Ehata, Hiroshi Takayanagi, Masanori Tsutsumi, Ryunosuke Muro, Tatsuo Asano, Kazuo Okamoto, Tadashi Okamura, K. Hashimoto, Takeshi Nitta, Yuta Nakai, Ayako Suematsu
Rok vydání: 2019
Předmět:
Zdroj: Nature Metabolism. 1:868-875
ISSN: 2522-5812
DOI: 10.1038/s42255-019-0104-1
Popis: 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. Asano et al. dissect the functional difference between the soluble and membrane-bound forms of RANKL. Membrane-bound RANKL is sufficient for most physiological RANKL functions, whereas soluble RANKL promotes bone metastases by stimulating tumour cell migration to bone, without affecting tumour cell growth or osteoclast differentiation.
Databáze: OpenAIRE
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