RANKL as a key figure in bridging between the bone and immune system: Its physiological functions and potential as a pharmacological target.

RANKL is a key molecule that bridges the bone and immune systems. RANKL stimulation activates a signaling pathway downstream of RANK, thereby determining the extent of bone resorption by inducing osteoclast maturation. The signaling pathway also regulates the development of different lymphoid organs, including the thymus, lymph nodes, and Peyer's patches, and plays an essential role in the establishment of immune tolerance. Such characteristics have continued to attract the attention of many researchers, even though it is now more than 20 years since RANKL was identified as a novel member of the TNF superfamily. Recently, we found that RANKL can function not only as a signal input molecule but also as a signal receptor to activate the RANKL reverse signaling pathway, which mediates the coupling between bone resorption and formation. This new finding may provide an important basis for elucidating the complex physiological roles played by RANKL.