First mouse model for combined osteogenesis imperfecta and Ehlers-Danlos syndrome

J Bone Miner Res. 2014 Jun;29(6):1412-23. doi: 10.1002/jbmr.2177.

Abstract

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.

Keywords: BONE MINERAL DENSITY; COLLAGEN; MINERALIZATION; OSTEOBLAST; OSTEOCLAST.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorptiometry, Photon
  • Alternative Splicing / genetics
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Bone Matrix / pathology
  • Bone Remodeling
  • Bone and Bones / diagnostic imaging
  • Bone and Bones / pathology
  • Bone and Bones / ultrastructure
  • Calcification, Physiologic
  • Collagen Type I / chemistry
  • Collagen Type I / genetics
  • Collagen Type I / ultrastructure
  • Collagen Type I, alpha 1 Chain
  • Disease Models, Animal*
  • Ehlers-Danlos Syndrome / complications*
  • Ehlers-Danlos Syndrome / physiopathology
  • Femur / pathology
  • Male
  • Mice
  • Molecular Sequence Data
  • Mutation / genetics
  • Osteogenesis Imperfecta / complications*
  • Osteogenesis Imperfecta / physiopathology
  • Protein Structure, Tertiary
  • Stromal Cells / metabolism
  • Stromal Cells / pathology

Substances

  • Collagen Type I
  • Collagen Type I, alpha 1 Chain