Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK.
Département d'Informatique, Université de Poitiers, 86073 Poitiers Cedex 9, France.
Dis Model Mech. 2022 Sep 1;15(9). doi: 10.1242/dmm.049428. Epub 2022 Sep 28.
The osteogenesis imperfecta murine (oim) model with solely homotrimeric (α1)3 type I collagen, owing to a dysfunctional α2(I) collagen chain, has a brittle bone phenotype, implying that the (α1)2(α2)1 heterotrimer is required for physiological bone function. Here, we comprehensively show, for the first time, that mice lacking the α2(I) chain do not have impaired bone biomechanical or structural properties, unlike oim homozygous mice. However, Mendelian inheritance was affected in male mice of both lines, and male mice null for the α2(I) chain exhibited age-related loss of condition. Compound heterozygotes were generated to test whether gene dosage was responsible for the less-severe phenotype of oim heterozygotes, after allelic discrimination showed that the oim mutant allele was not downregulated in heterozygotes. Compound heterozygotes had impaired bone structural properties compared to those of oim heterozygotes, albeit to a lesser extent than those of oim homozygotes. Hence, the presence of heterotrimeric type I collagen in oim heterozygotes alleviates the effect of the oim mutant allele, but a genetic interaction between homotrimeric type I collagen and the oim mutant allele leads to bone fragility.
由于α2(I) 胶原链功能障碍，仅具有同三聚体（α1）3 型 I 胶原的成骨不全症小鼠（oim）模型具有易碎骨表型，这意味着（α1）2(α2)1 异三聚体是生理骨骼功能所必需的。在这里，我们首次全面表明，与 oim 纯合子小鼠不同，缺乏α2(I) 链的小鼠没有骨生物力学或结构特性受损。然而，这两种品系的雄性小鼠的孟德尔遗传均受到影响，并且缺乏α2(I) 链的雄性小鼠表现出与年龄相关的状态丧失。我们生成了杂合子以测试基因剂量是否是 oim 杂合子表型较轻的原因，等位基因鉴别表明 oim 突变等位基因在杂合子中没有下调。与 oim 杂合子相比，复合杂合子的骨结构特性受损，尽管程度不及 oim 纯合子。因此，oim 杂合子中存在异三聚体 I 型胶原减轻了 oim 突变等位基因的影响，但同三聚体 I 型胶原和 oim 突变等位基因之间的遗传相互作用导致骨骼脆弱。
