Mendelian Disorders of RANKL/OPG/RANK/NF-κB Signaling

Revelation that the RANKL/OPG/RANK/NF-κB signaling pathway is a key modulator of osteoclast (OC) formation and action began in the 1990s with the discoveries of three new members of the tumor necrosis factor (TNF) superfamily (RANKL, OPG, and RANK). Soon after, genetically altered mice disclosed importance for these proteins in bone biology. Binding of RANKL to RANK promotes osteoclastogenesis and increased skeletal remodeling mediated through NF-κB signaling, whereas coupling of RANKL instead to its "decoy receptor" OPG inhibits this pathway. Subsequently, the significance of these proteins for humans was highlighted by the discoveries that mutation of the genes that encode RANKL (TNFSF11), OPG (TNFRSF11B), and RANK (TNFRSF11A) explain several ultrarare but highly instructive Mendelian diseases that alter osteoclastogenesis and OC action. Those that activate the pathway (familial expansile osteolysis, early-onset Paget's disease of bone, expansile skeletal hyperphosphatasia, panostotic expansile bone disease, and juvenile Paget's disease) resemble classic Paget's disease of bone. Those that deactivate the pathway cause "OC-poor" osteopetrosis due to impaired OC formation. In 2016, neonatal high bone mass became the newest heritable entity of this pathway and revealed the first mutation identified within the five-member NF-κB complex itself. This chapter reviews the clinical and laboratory features as well as the etiology and pathogenesis of these intriguing disorders.