Insertion mutation in Tnfrsf11a causes a Paget's disease-like phenotype in heterozygous mice and osteopetrosis in homozygous mice

Nerea Alonso, Sachin Wani, Lorraine Rose, Rob J Van't Hof, Stuart H Ralston, Omar M E Albagha

Research output: Contribution to journalArticlepeer-review

Abstract

Early onset familial Paget's disease of bone (EoPDB), familial expansile osteolysis and expansile skeletal hyperphosphatasia are related disorders caused by insertion mutations in exon 1 of the TNFRSF11A gene which encodes receptor activator of nuclear factor kappa B (RANK) protein. To understand the mechanisms underlying these disorders, we developed a mouse model carrying the 75dup27 mutation which causes EoPDB. Mice heterozygous for the mutation (Tnfrsf11a75dup27/- ) developed a PDB-like disorder with focal osteolytic lesions in the hind limbs with increasing age. Treatment of these mice with zoledronic acid completely prevented the development of lesions. Studies in vitro showed that RANKL-induced osteoclast formation and signaling was impaired in bone marrow cells from Tnfrsf11a75dup27/- animals, but that osteoclast survival was increased independent of RANKL stimulation. Surprisingly, Tnfrsf11a75dup27/75dup27 homozygotes had osteopetrosis at birth, with complete absence of osteoclasts. Bone marrow cells from these mice failed to form osteoclasts in response to RANKL and M-CSF stimulation. This intriguing study has shown that in heterozygous form, the 75dup27 mutation causes focal osteolytic lesions in vivo reminiscent of the human disorder and extends osteoclast survival independently of RANKL signaling. In homozygous form however, the mutation causes osteopetrosis due to failure of osteoclast formation and insensitivity to RANKL stimulation. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalJournal of Bone and Mineral Research
Early online date16 Mar 2021
DOIs
Publication statusE-pub ahead of print - 16 Mar 2021

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