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

AbstractCommon genetic variants at theRIN3 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 mouseRin3 gene (Rin3−/−) as compared with wild-type littermates. TheRin3−/− 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 (p = 0.002) and at 52 weeks were 15.8 ± 9.5 vs. 8.5 ± 4.2 (p = 0.002). No differences were observed in femoral cortical bone parameters with the exception of marrow diameter which was significantly smaller in 52-week-oldRin3−/− mice compared to wild type: (0.43 mm ± 0.1 vs. 0.57 mm ± 0.2 (p = 0.001). Bone histomorphometry showed a lower osteoclast surface / bone surface (Oc.S/BS%) at 8 weeks inRin3−/− mice compared to wild type (24.1 ± 4.7 vs. 29.7 ± 6.6;p = 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 inRin3−/− mice (24.4 ± 6.4 vs. 16.5 ± 3.8,p = 0.003). We conclude thatRin3 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 ...
Source: Calcified Tissue International - Category: Orthopaedics Source Type: research