Genetic disorders associated with the RANKL/OPG/RANK pathway

The RANKL/OPG/RANK signalling pathway is a major regulatory system for osteoclast formation and activity. Mutations in TNFSF11, TNFRSF11B and TNFRSF11A cause defects in bone metabolism and development, thereby leading to skeletal disorders with changes in bone density and/or morphology. To date, nine kinds of monogenic skeletal diseases have been found to be causally associated with TNFSF11, TNFRSF11B and TNFRSF11A mutations. These diseases can be divided into two types according to the mutation effects and the resultant pathogenesis. One is caused by the mutations inducing constitutional RANK activation or OPG deficiency, which increase osteoclastogenesis and accelerate bone turnover, resulting in juvenile Paget’s disease 2, Paget disease of bone 2, familial expansile osteolysis, expansile skeletal hyperphosphatasia, panostotic expansile bone disease, and Paget disease of bone 5. The other is caused by the de-activating mutations in TNFRSF11A or TNFSF11, which decrease osteoclastogenesis and elevate bone density, resulting in osteopetrosis, autosomal recessive 2 and 7, and dysosteosclerosis. Here we reviewed the current knowledge about these genetic disorders with paying particular attention to the updating genotype–phenotype association in the TNFRSF11A-caused diseases.