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First Mouse Model for Combined Osteogenesis Imperfecta and Ehlers‐Danlos Syndrome
Author(s) -
Chen Frieda,
Guo Ruolin,
Itoh Shousaku,
Moreno Luisa,
Rosenthal Esther,
Zappitelli Tanya,
Zirngibl Ralph A,
Flenniken Ann,
Cole William,
Grynpas Marc,
Osborne Lucy R,
Vogel Wolfgang,
Adamson Lee,
Rossant Janet,
Aubin Jane E
Publication year - 2014
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.2177
Subject(s) - osteogenesis imperfecta , type i collagen , chemistry , osteoblast , ehlers–danlos syndrome , bone resorption , endocrinology , stromal cell , collagen, type i, alpha 1 , bone mineral , medicine , microbiology and biotechnology , anatomy , extracellular matrix , osteoporosis , biology , pathology , in vitro , biochemistry
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 ∼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. © 2014 American Society for Bone and Mineral Research.