[Discovery of RANKL and the current and future impact of its research]

Discovery of RANKL (receptor activator of NF-κB ligand) had an impact on identification of the mechanisms regulating osteoclast differentiation and function, resulting in establishment of research field bridging bone biology and immunology (osteoimmunology), and development of a human anti-RANKL monoclonal antibody (denosumab). Denosumab has been clinically available for treatment of osteoporosis and cancer-induced bone diseases in many countries. Denosumab is a so-called blockbuster of which sales amount was 5.3 billion US dollars in 2021. I will discuss the intense competition between Amgen Inc. and us regarding discovery of RANKL. One of the recent topics is the identification of RANKL reverse signaling with a RANKL-binding peptide, W9 known as a RANKL antagonist. The RANKL reverse signaling stimulates differentiation of osteoblasts and bone formation. The findings revealed the RANKL-RANK (a receptor of RANKL) dual signaling in coupling between bone resorption and bone formation. Interestingly, W9 also stimulates differentiation of chondrocytes and repairs defect of articular cartilage regardless of RANKL. Identification of the mechanisms will be useful for development of pharmaceuticals treating osteoarthritis. I also suggest possible applications of anti-RANKL antibody (anti-RANKL) to the treatment of cancer patients. RANKL has an important role in development of medullary thymic epithelial cells (mTECs) establishing self-tolerance. Anti-RANKL potentiates anticancer immune responses thorough regeneration of tumor-reactive T-cells by inhibiting mTEC development. I expect the synergy of anti-RANKL and immune checkpoint inhibitors such as anti-CTLA-4 antibody and anti-PD-1 antibody for immuno-oncology. Several clinical trials are currently in progress. It is likely that cancers will not be incurable diseases in the near future.