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

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.

A rare haplotype in the upstream regulatory region of COL1A1 is associated with reduced bone quality and hip fracture.

Three polymorphisms have been identified in the 5' regulatory region of the COL1A1 gene at positions -1997 (rs1107946), -1663 (rs2412298), and +1245G/T (rs1800012), which combine to form haplotypes that have been associated with BMD in several populations. These polymorphisms and haplotypes have not thus far been studied in relation to biomechanical properties of bone or fracture risk. Genotypes and haplotypes of the COL1A1 gene were related to the biomechanical properties of bone ex vivo in samples of bone tissue obtained from the femoral head of 98 consecutive patients undergoing surgery for low-trauma hip fractures. Genotype and haplotype frequencies in the hip fracture cases were compared with 3418 population-based controls recruited from the same region. All three polymorphisms were associated with material density of the bone core, yield strength, and toughness. The association between -1663InsdelT and +1245G/T alleles, yield strength, and toughness remained significant after adjusting for material density of the core and other confounding factors. A haplotype comprising the unfavorable allele at all three polymorphic sites (-1997T/-1663delT/+1245T) was also associated with yield strength, modulus, and toughness after adjusting for confounding factors. This haplotype was carried by 19/94 (20.2%) patients with hip fracture compared with only 2/3399 (0.06%) female controls drawn from the general population (p < 0.0001). In contrast, there was no significant difference between cases and controls in genotype distribution for the individual polymorphisms. This study shows that common genetic variants in the 5' regulatory region of COL1A1 are associated with biomechanical properties of bone and reduced bone quality by mechanisms independent of their effects on BMD. The biomechanically unfavorable allele at each polymorphic site defines a haplotype that is extremely rare in the general population but that is approximately 400-fold enriched in hip fracture patients. This haplotype may have clinical value as a genetic marker for susceptibility to hip fracture, and further studies to investigate this possibility would be of interest.