First Mouse Model for Combined Osteogenesis Imperfecta and Ehlers-Danlos Syndrome

被引：69

作者：

Chen, Frieda ^{[1
]}

Guo, Ruolin ^{[1
]}

Itoh, Shousaku ^{[1
]}

Moreno, Luisa ^{[2
]}

Rosenthal, Esther ^{[1
]}

Zappitelli, Tanya ^{[3
]}

Zirngibl, Ralph A. ^{[1
]}

Flenniken, Ann ^{[4
]}

Cole, William ^{[5
]}

Grynpas, Marc ^{[2
,6
]}

Osborne, Lucy R. ^{[1
,4
,7
]}

Vogel, Wolfgang ^{[6
]}

Adamson, Lee ^{[4
,8
,9
]}

Rossant, Janet ^{[1
,4
,10
]}

Aubin, Jane E. ^{[1
,4
]}

机构：

[1] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada

[2] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada

[3] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 1A8, Canada

[4] Toronto Ctr Phenogen, Ctr Modeling Human Dis, Toronto, ON, Canada

[5] Hosp Sick Children, Div Orthoped, Toronto, ON M5G 1X8, Canada

[6] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A8, Canada

[7] Univ Toronto, Dept Med, Toronto, ON M5S 1A8, Canada

[8] Univ Toronto, Heart & Stroke Richard Lewar Ctr Excellence, Toronto, ON M5S 1A8, Canada

[9] Univ Toronto, Dept Obstet & Gynecol, Toronto, ON M5S 1A8, Canada

[10] Hosp Sick Children, Program Dev & Stem Cell Biol, Toronto, ON M5G 1X8, Canada

来源：

JOURNAL OF BONE AND MINERAL RESEARCH | 2014年 / 29卷 / 06期

基金：

加拿大健康研究院;

关键词：

OSTEOBLAST; OSTEOCLAST; MINERALIZATION; COLLAGEN; BONE MINERAL DENSITY; COLLAGEN MUTATION DATABASE; SYNDROME TYPE-VI; SYNDROME TYPE-I; TRANSGENIC MICE; COL5A1; GENE; BONE FRAGILITY; MURINE MODEL; PHENOTYPE; EXPRESSION; HAPLOINSUFFICIENCY;

D O I：

10.1002/jbmr.2177

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

By using a genome-wide N-ethyl-N-nitrosourea (ENU)-induced dominant mutagenesis screen in mice, a founder with low bone mineral density (BMD) was identified. Mapping and sequencing revealed a T to C transition in a splice donor of the collagen alpha1 type I (Col1a1) gene, resulting in the skipping of exon 9 and a predicted 18-amino acid deletion within the N-terminal region of the triple helical domain of Col1a1. Col1a1(Jrt)/+ mice were smaller in size, had lower BMD associated with decreased bone volume/tissue volume (BV/TV) and reduced trabecular number, and furthermore exhibited mechanically weak, brittle, fracture-prone bones, a hallmark of osteogenesis imperfecta (OI). Several markers of osteoblast differentiation were upregulated in mutant bone, and histomorphometry showed that the proportion of trabecular bone surfaces covered by activated osteoblasts (Ob.S/BS and N.Ob/BS) was elevated, but bone surfaces undergoing resorption (Oc.S/BS and N.Oc/BS) were not. The number of bone marrow stromal osteoprogenitors (CFU-ALP) was unaffected, but mineralization was decreased in cultures from young Col1a1(Jrt)/+ versus +/+ mice. Total collagen and type I collagen content of matrices deposited by Col1a1(Jrt)/+ dermal fibroblasts in culture was approximate to 40% and 30%, respectively, that of +/+ cells, suggesting that mutant collagen chains exerted a dominant negative effect on type I collagen biosynthesis. Mutant collagen fibrils were also markedly smaller in diameter than +/+ fibrils in bone, tendon, and extracellular matrices deposited by dermal fibroblasts in vitro. Col1a1(Jrt)/+ mice also exhibited traits associated with Ehlers-Danlos syndrome (EDS): Their skin had reduced tensile properties, tail tendon appeared more frayed, and a third of the young adult mice had noticeable curvature of the spine. Col1a1(Jrt)/+ is the first reported model of combined OI/EDS and will be useful for exploring aspects of OI and EDS pathophysiology and treatment. (c) 2014 American Society for Bone and Mineral Research.

引用

页码：1412 / 1423

页数：12

共 68 条

[1]

Mutations in the Gene Encoding the RER Protein FKBP65 Cause Autosomal-Recessive Osteogenesis Imperfecta [J].