[Regulation of central tolerance by RANKL signaling]

RANKL (receptor activator of NF-κB ligand) is a member of TNF (tumor-necrosis factor) family cytokine. Several genetic studies indicated critical roles of RANKL and its receptor RANK in bone homeostasis. RANKL-RANK signal regulates differentiation, survival and activation of osteoclasts. Therefore, suppression of the RANKL signal would be a promising strategy for interventions in osteoporosis or rheumatoid arthritis. Indeed, humanized anti-RANKL neutralizing antibody is coming onto the market as an antiresorptive agent for osteoporosis treatment. In addition to the role on bone homeostasis, several studies suggested that the RANKL-RANK interaction regulates immune response and development. For instance, RANKL was previously identified as a survival factor for dendritic cells. Moreover, we and other groups reported that the RANKL signal contributes to development of medullary thymic epithelial cells (mTECs) . mTECs ectopically express and present a number of tissue restricted antigens (e.g. insulin) of which expressions are in part regulated by autoimmune regulator (Aire) , a factor responsible for a genetic human autoimmune disorder, thereby eliminating T cells reactive to these tissue restricted self-antigens. As result, RANKL is involved in establishment of self-tolerance in thymus by regulating the development of mTECs expressing Aire and tissue restricted antigens.