Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone

T Asano, K Okamoto, Y Nakai, M Tsutsumi, R Muro… - Nature …, 2019 - nature.com
T Asano, K Okamoto, Y Nakai, M Tsutsumi, R Muro, A Suematsu, K Hashimoto, T Okamura…
Nature Metabolism, 2019nature.com
Receptor activator of NF-κB ligand (RANKL) is a multifunctional cytokine known to affect
immune and skeletal systems, as well as oncogenesis and metastasis,,–. RANKL is
synthesized as a membrane-bound molecule, and cleaved into its soluble form by
proteases,–. As the soluble form of RANKL does not contribute greatly to bone remodelling
or ovariectomy-induced bone loss, whether soluble RANKL has a role in pathological
settings remains unclear. Here we show that soluble RANKL promotes the formation of …
Abstract
Receptor activator of NF-κB ligand (RANKL) is a multifunctional cytokine known to affect immune and skeletal systems, as well as oncogenesis and metastasis, , –. RANKL is synthesized as a membrane-bound molecule, and cleaved into its soluble form by proteases, –. As the soluble form of RANKL does not contribute greatly to bone remodelling or ovariectomy-induced bone loss, 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), –, 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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