Heritable disorders of the RANKL/OPG/RANK signaling pathway

Figure 7 summarizes the heritable disorders identified to date that directly involve the RANKL/OPG/RANK signaling pathway in humans. Activating mutations in TNFRSF11A encoding RANK and deactivating mutations in TNFRSF11B encoding OPG cause systemic bone disease (FEO, PDB2, ESH and JPD) featuring accelerated bone turnover, low bone mass, deafness early in life, and loss of dentition by enhancing signaling. No human disease has been identified involving defects in the TNFSF11 gene encoding RANKL. Despite genetic bases for these autosomal dominant and recessive conditions involving bone cell receptors, focal expansile osteolytic lesions are common and can occur perhaps from further local activation of osteoclast-mediated bone resorption following trauma. These disorders resemble PDB which can be inherited as an autosomal dominant trait with focal osteolytic disease, sometimes with deafness and tooth loss, and increasingly associated with mutations, but in other genes.