Targeted Inactivation of Rin3 Increases Trabecular Bone Mass by Reducing Bone Resorption and Favouring Bone Formation

Vallet, Mahéva, Sophocleous, Antonia, Törnqvist, Anna E, Azfer, Asim, Hof, Rob van’t, Albagha, Omar ME and Ralston, Stuart H
(2021) Targeted Inactivation of Rin3 Increases Trabecular Bone Mass by Reducing Bone Resorption and Favouring Bone Formation. Calcified Tissue International, 109 (1). pp. 92-102.

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<jats:title>Abstract</jats:title><jats:p>Common genetic variants at the <jats:italic>RIN3</jats:italic> locus on chromosome 14q32 predispose to Paget’s disease of bone (PDB) but the mechanisms by which they do so are unknown. Here, we analysed the skeletal phenotype of female mice with targeted inactivation of the mouse <jats:italic>Rin3</jats:italic> gene (<jats:italic>Rin3</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup>) as compared with wild-type littermates. The <jats:italic>Rin3</jats:italic><jats:sup><jats:italic>−</jats:italic>/<jats:italic>−</jats:italic></jats:sup> mice had higher trabecular bone volume (BV/TV%) compared with wild type. Mean ± standard deviation values at the distal femur at 8 weeks were 9.0 ± 2.5 vs. 7.0 ± 1.5 (<jats:italic>p</jats:italic> = 0.002) and at 52 weeks were 15.8 ± 9.5 vs. 8.5 ± 4.2 (<jats:italic>p</jats:italic> = 0.002). No differences were observed in femoral cortical bone parameters with the exception of marrow diameter which was significantly smaller in 52-week-old <jats:italic>Rin3</jats:italic><jats:sup><jats:italic>−</jats:italic>/<jats:italic>−</jats:italic></jats:sup> mice compared to wild type: (0.43 mm ± 0.1 vs. 0.57 mm ± 0.2 (<jats:italic>p</jats:italic> = 0.001). Bone histomorphometry showed a lower osteoclast surface / bone surface (Oc.S/BS%) at 8 weeks in <jats:italic>Rin3</jats:italic><jats:sup><jats:italic>−</jats:italic>/<jats:italic>−</jats:italic></jats:sup> mice compared to wild type (24.1 ± 4.7 vs. 29.7 ± 6.6; <jats:italic>p</jats:italic> = 0.025) but there were no significant differences in markers of bone formation at this time. At 52 weeks, Oc.S/BS did not differ between genotypes but single labelled perimeter (SL.Pm/B.Pm (%)) was significantly higher in <jats:italic>Rin3</jats:italic><jats:sup><jats:italic>−</jats:italic>/<jats:italic>−</jats:italic></jats:sup> mice (24.4 ± 6.4 vs. 16.5 ± 3.8, <jats:italic>p</jats:italic> = 0.003). We conclude that <jats:italic>Rin3</jats:italic> negatively regulates trabecular bone mass in mice by inhibiting osteoclastic bone resorption and favouring bone formation. Our observations also suggest that the variants that predispose to PDB in humans probably do so by causing a gain-in-function of <jats:italic>RIN3</jats:italic>.</jats:p>

Item Type: Article
Uncontrolled Keywords: Paget&#8217, s disease, Osteoclast, Genetic, RIN3
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences
Depositing User: Symplectic Admin
Date Deposited: 13 Apr 2021 07:26
Last Modified: 18 Jan 2023 22:53
DOI: 10.1007/s00223-021-00827-2
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