Common genetic variants at the RIN3 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 Rin3 gene (Rin3^−/−) as compared with wild-type littermates. The Rin3^−/− 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-old Rin3^−/− 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 in Rin3^−/− 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 in Rin3^−/− mice (24.4 ± 6.4 vs. 16.5 ± 3.8, p = 0.003). We conclude that Rin3 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 RIN3.

染色体 14q32 上RIN3基因座的常见遗传变异易患佩吉特骨病 (PDB)，但其发生机制尚不清楚。在这里，我们分析了小鼠Rin3基因 ( Rin3 ^-/- ) 靶向失活的雌性小鼠与野生型同窝仔鼠的骨骼表型。与野生型相比，Rin3 ^{- / -}小鼠的骨小梁体积（BV/TV%）更高。8 周时股骨远端的平均 ± 标准偏差值为 9.0 ± 2.5 对 7.0 ± 1.5 ( p = 0.002)，52 周时分别​​为 15.8 ± 9.5 对 8.5 ± 4.2 ( p= 0.002)。股骨皮质骨参数未观察到差异，但 52 周龄Rin3 ^{- / -}小鼠的骨髓直径明显小于野生型：（0.43 mm ± 0.1 vs. 0.57 mm ± 0.2 ( p = 0.001 ).与野生型相比， Rin3 ^{- / -}小鼠在第 8 周时的骨组织形态测量显示破骨细胞表面/骨表面 (Oc.S/BS%)较低（24.1 ± 4.7 对 29.7 ± 6.6； p = 0.025），但有此时骨形成标志物没有显着差异。在 52 周时，基因型之间的 Oc.S/BS 没有差异，但 Rin3 中的单标记周长 (SL.Pm/B.Pm (%)) 显着更高^{-/ -}小鼠（24.4 ± 6.4 对 16.5 ± 3.8，p = 0.003）。我们得出结论，Rin3通过抑制破骨细胞骨吸收和促进骨形成负调节小鼠的骨小梁质量。我们的观察还表明，人类易患 PDB 的变体可能是通过导致RIN3的功能增益来实现的。