Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone

Nat Metab. 2019 Sep;1(9):868-875. doi: 10.1038/s42255-019-0104-1. Epub 2019 Sep 2.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Neoplasms / secondary*
  • Bone Remodeling / physiology
  • Cell Differentiation / physiology
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Neoplasm Metastasis
  • Neoplasms / pathology*
  • Osteoclasts / cytology
  • Receptor Activator of Nuclear Factor-kappa B / genetics
  • Receptor Activator of Nuclear Factor-kappa B / physiology*

Substances

  • Receptor Activator of Nuclear Factor-kappa B