Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone

Receptor activator of NF-κB ligand (RANKL) is a multifunctional cytokine known to affect immune and skeletal systems, as well as oncogenesis and metastasis^1-4. RANKL is synthesized as a membrane-bound molecule, and cleaved into its soluble form by proteases^5-7. 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 (Tnfsf11^ΔS/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.