Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone
Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone
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DOI：
10.1038/s42255-019-0104-1
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发表时间：
2019-09-01
影响因子：
20.8
通讯作者：
Takayanagi, Hiroshi
中科院分区：
文献类型：
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作者：
Asano, Tatsuo;Okamoto, Kazuo;Takayanagi, Hiroshi
核因子-kappaB受体激活剂配体(RANKL)是一种多功能细胞因子，可影响免疫和骨骼系统以及肿瘤的发生和转移(1-4)。RANKL是以膜结合分子的形式合成的，并被蛋白酶(5-7)切割成可溶的形式。由于RANKL的可溶性形式对骨重建或卵巢切除引起的骨丢失没有很大的贡献[8]，目前尚不清楚可溶性RANKL是否在病理环境中起作用。在这里，我们展示了可溶性RANKL促进骨肿瘤转移的形成。选择性缺乏可溶性RANKL的小鼠(Tnfsf11(德尔塔S/德尔塔S))(5-7，9)具有正常的骨稳态和正常的免疫系统，但在心内注射表达RANK的黑色素瘤和乳腺癌细胞后，骨转移数量显著减少。可溶性RANKL的缺失不影响转移灶或肿瘤向非骨骼组织转移的破骨细胞数量。因此，可溶性RANKL对骨和免疫系统的生理调节是必不可少的，但在促进骨转移方面具有独特而关键的作用。
Receptor activator of NF-kappa B 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 loss(8), 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(Delta S/Delta S))(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.