Osteoclast Signal Transduction Pathways: The RANKL/RANK System

Binding of RANKL to its receptor, RANK, on osteoclast precursors recruits TNF receptor-associated factors, which are adaptor proteins and ubiquitin ligases that regulate NF-κB, JNK, c-Fos, NFATc1 ERK, p38, NFATc1 and AKT signaling to control osteoclast formation and activity in normal and pathologic bone resorption. RANKL/RANK signaling also regulates immune cell functions and has been implicated in the development of breast cancer, cardiovascular disease and diabetes and can be inhibited by denosumab, a monoclonal antibody that binds to RANKL. Recent studies have indicated that RANK is expressed by osteoblast progenitors and that reverse signaling occurs through RANKL on osteoblastic cells can regulate osteoblast formation, raising the possibility that anabolic therapy might be possible through this pathway.