Genetic disorders associated with the RANKL/OPG/RANK pathway
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INVITED REVIEW
Genetic disorders associated with the RANKL/OPG/RANK pathway Jing‑Yi Xue1,2 · Shiro Ikegawa1 · Long Guo1 Received: 30 July 2020 / Accepted: 20 August 2020 © The Japanese Society Bone and Mineral Research and Springer Japan KK, part of Springer Nature 2020
Abstract 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. Keywords RANKL · OPG · RANK · Disease · Osteoclast
Osteoclast and RANKL/OPG/RANK Bone metabolism involves multiple, but coordinated cellular and molecular events, which lead to dynamic balance between bone formation and bone resorption. Osteoclast, a monocyte–macrophage lineage cell in charge of bone resorption is regulated by numerous factors. The final two effectors are receptor activator of nuclear factor-κB ligand (RANKL; also known as TNFSF11) and osteoprotegerin (OPG; also known as TNFRSF11B). Both are secreted by osteoblastic lineage cells. RANKL binds to its receptor, Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00774-020-01148-4) contains supplementary material, which is available to authorized users. * Shiro Ikegawa [email protected]‑tokyo.ac.jp * Long Guo [email protected] 1
Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, 4‑6‑1 Minato‑ku, Tokyo 108‑8639, Japan
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
2
receptor activator of nuclear factor-κB (RANK; also known as TNFRSF11A) on cells of the myeloid lineage and induces differentiation and activation of osteoclast precursors. OPG is a soluble decoy receptor for RANKL which prevents the RANKL–RANK binding and thus inhibits osteoclast maturation [1]. On the other hand, maturing osteoclasts secrete vesicular RANK which activates the RANKL reverse signaling
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