Receptor activator of nuclear factor-κB ligand (RANKL)/RANK/osteoprotegerin system in bone and other tissues

The receptor activator of nuclear factor-kappa B ligand (RANKL)/RANK/osteoprotegerin (OPG) system was identified in the late 1990s, ending the search for the specific factors expressed by osteoblasts and stromal cells in order to regulate osteoclastogenesis. The identification of the RANKL/RANK/OPG system was a breakthrough in bone biology; however, the system not only works as a. dominant mediator in osteoclast activation, formation and survival, but also functions in other tissues, including the mammary glands, brain and lymph nodes. Evidence has indicated that the existence of the RANKL/RANK/OPG system in these tissues suggests that it may have specific functions beyond those in bone. Disorders of the RANKL/RANK/OPG system are associated with certain human diseases, including postmenopausal osteoporosis, rheumatoid arthritis (RA), bone tumors and certain bone metastatic tumors. Genetic studies have indicated that the RANKL/RANK/OPG system may be a key regulator in the formation of lymph nodes and in the autoimmune disease RA, which further suggests that the immune system may interact with the RANKL/RANK/OPG system. The present review aimed to provide an overview of the role of the RANKL/RANK/OPG system in osteoclastogenesis, bone disease and tissues beyond bone.