RANKL has key roles in the immune and skeletal systems, as well as in oncogenesis and metastasis. The cytokine occurs in two forms — soluble and membrane-bound — and the precise role of the soluble form has so far been unclear. New research published in Nature Metabolism now suggests that soluble RANKL is not required for physiological regulation of the skeletal and immune systems; however, soluble RANKL has an important role in the development of bone metastases.
“To clarify the role of soluble RANKL in vivo, we generated soluble RANKL-deficient mice by genetically deleting the cleavage sites of the extracellular domain of RANKL using the CRISPR–Cas9 system,” explain authors Kazuo Okamoto and Hiroshi Takayanagi. Various analyses showed that these Tnfsf11ΔS/ΔS mice grew normally and had no obvious defects. They did not differ from control littermates in terms of growth, skeletal development, immune system function or bone remodelling, which demonstrates that soluble RANKL is not involved in these processes.
Next, the researchers injected wild-type and Tnfsf11ΔS/ΔS mice with B16F10 Red-FLuc cells (a melanoma cell line) to assess the role of soluble RANKL in tumour progression and metastases. Rapid metastasis into the long bones was seen in the wild-type mice. By contrast, tumour progression was reduced in the Tnfsf11ΔS/ΔS mice. Similar results were seen with the use of E0771-Luc cells (a breast cancer cell line). “Moreover, soluble RANKL deficiency affected neither osteoclasts at the metastasis site nor tumour metastasis to non-skeletal tissues,” explain Okamoto and Takayanagi. “Thus, we showed that soluble RANKL is physiologically dispensable but promotes bone metastasis via directly triggering the migration of tumour cells to bone.”
“soluble RANKL has an important role in the development of bone metastases”
The researchers hope that their results will lead to the development of new therapies to specifically target the metastatic process. “We would like to establish strategies to block soluble RANKL alone without affecting membrane-bound RANKL or the production process of soluble RANKL in bone of patients with cancer,” say Okamoto and Takayanagi.
Asano, T. et al. Soluble RANKL is physiologically dispensable but accelerates tumour metastasis to bone. Nat. Metab. https://doi.org/10.1038/s42255-019-0104-1 (2019)
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Greenhill, C. Function of soluble RANKL deciphered. Nat Rev Endocrinol 15, 628 (2019). https://doi.org/10.1038/s41574-019-0264-9