First mouse model for combined osteogenesis imperfecta and Ehlers-Danlos syndrome.
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.
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
Frieda
F
Chen
Ruolin
R
Guo
Shousaku
S
Itoh
Luisa
L
Moreno
Esther
E
Rosenthal
Tanya
T
Zappitelli
Ralph A
RA
Zirngibl
Ann
A
Flenniken
William
W
Cole
Marc
M
Grynpas
Lucy R
LR
Osborne
Wolfgang
W
Vogel
Lee
L
Adamson
Janet
J
Rossant
Jane E
JE
Aubin
D015502:Absorptiometry, Photon; D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001857:Bone Matrix / Q000473:pathology; D016723:Bone Remodeling; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology / Q000648:ultrastructure; D002113:Calcification, Physiologic; D024042:Collagen Type I / Q000737:chemistry / Q000235:genetics / Q000648:ultrastructure; D000090602:Collagen Type I, alpha 1 Chain; D004195:Disease Models, Animal; D004535:Ehlers-Danlos Syndrome / Q000150:complications* / Q000503:physiopathology; D005269:Femur / Q000473:pathology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010013:Osteogenesis Imperfecta / Q000150:complications* / Q000503:physiopathology; D017434:Protein Structure, Tertiary; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain
BONE MINERAL DENSITY; COLLAGEN; MINERALIZATION; OSTEOBLAST; OSTEOCLAST