期刊
JOURNAL OF BONE AND MINERAL RESEARCH
卷 29, 期 6, 页码 1412-1423出版社
WILEY-BLACKWELL
DOI: 10.1002/jbmr.2177
关键词
OSTEOBLAST; OSTEOCLAST; MINERALIZATION; COLLAGEN; BONE MINERAL DENSITY
资金
- Canadian Institutes of Health Research (CIHR) [MOP 69198]
- Canadian Institutes of Health Research (CIHR Distinguished Scientist Award)
- Canadian Institutes of Health Research (CIHR/Osteoporosis Canada Fellowship)
- Genome Canada
- Ontario Genomic Institute
- Canadian Arthritis Network
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.
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