PLoS Genetics (Feb 2008)

ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta.

  • Thomas S Lisse,
  • Frank Thiele,
  • Helmut Fuchs,
  • Wolfgang Hans,
  • Gerhard K H Przemeck,
  • Koichiro Abe,
  • Birgit Rathkolb,
  • Leticia Quintanilla-Martinez,
  • Gabriele Hoelzlwimmer,
  • Miep Helfrich,
  • Eckhard Wolf,
  • Stuart H Ralston,
  • Martin Hrabé de Angelis

DOI
https://doi.org/10.1371/journal.pgen.0040007
Journal volume & issue
Vol. 4, no. 2
p. e7

Abstract

Read online

Osteogenesis imperfecta is an inherited disorder characterized by increased bone fragility, fractures, and osteoporosis, and most cases are caused by mutations affecting the type I collagen genes. Here, we describe a new mouse model for Osteogenesis imperfecta termed Aga2 (abnormal gait 2) that was isolated from the Munich N-ethyl-N-nitrosourea mutagenesis program and exhibited phenotypic variability, including reduced bone mass, multiple fractures, and early lethality. The causal gene was mapped to Chromosome 11 by linkage analysis, and a C-terminal frameshift mutation was identified in the Col1a1 (procollagen type I, alpha 1) gene as the cause of the disorder. Aga2 heterozygous animals had markedly increased bone turnover and a disrupted native collagen network. Further studies showed that abnormal proalpha1(I) chains accumulated intracellularly in Aga2/+ dermal fibroblasts and were poorly secreted extracellularly. This was associated with the induction of an endoplasmic reticulum stress-specific unfolded protein response involving upregulation of BiP, Hsp47, and Gadd153 with caspases-12 and -3 activation and apoptosis of osteoblasts both in vitro and in vivo. These studies resulted in the identification of a new model for Osteogenesis imperfecta, and identified a role for intracellular modulation of the endoplasmic reticulum stress-associated unfolded protein response machinery toward osteoblast apoptosis during the pathogenesis of disease.