Receptor activator of NF-κB ligand (RANKL) is a multifunctional cytokine known to affect immune and skeletal systems, as well as oncogenesis and metastasis^1,2,3,4. RANKL is synthesized as a membrane-bound molecule, and cleaved into its soluble form by proteases^5,6,7. 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 (Tnfsf11^ΔS/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.

NF-κB配体的受体激活剂（RANKL）是一种多功能的细胞因子，已知会影响免疫系统和骨骼系统，以及肿瘤发生和转移^1,2,3,4。RANKL被合成为膜结合分子，并被蛋白酶^5,6,7切割成可溶形式。由于RANKL的可溶形式对骨重塑或卵巢切除术引起的骨质流失并没有太大贡献⁸，因此尚不清楚可溶RANKL是否在病理环境中起作用。在这里，我们显示可溶性RANKL促进骨中肿瘤转移的形成。选择性缺乏可溶性RANKL（Tnfsf11ΔS ^/ΔS）的^{小鼠5,6,7,9}具有正常的骨稳态和发展正常的免疫系统，但在心脏内注射表达RANK的黑色素瘤和乳腺癌细胞后，骨转移的数目明显减少。可溶性RANKL的删除不影响转移性病变中的破骨细胞数量或肿瘤转移至非骨骼组织。因此，可溶性RANKL对于骨骼和免疫系统的生理调节是必不可少的，但是在促进骨转移方面具有独特和关键的作用。