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 Hrabe de Angelis

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Abstract

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 pro alpha 1( 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.

Original languageEnglish
Article numbere7
Number of pages11
JournalPLoS Genetics
Volume4
Issue number2
DOIs
Publication statusPublished - 1 Feb 2008

Keywords

  • carboxyl-terminal propeptide
  • endoplasmic-reticulum stress
  • I collagen
  • differential expression
  • bone histomorphometry
  • pro-ALPHA-1(I) chain
  • transgenic mice
  • binding sites
  • murine model
  • lethal

Cite this

Lisse, T. S., Thiele, F., Fuchs, H., Hans, W., Przemeck, G. K. H., Abe, K., ... de Angelis, M. H. (2008). ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta. PLoS Genetics, 4(2), [e7]. https://doi.org/10.1371/journal.pgen.0040007

ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta. / Lisse, Thomas S; Thiele, Frank; Fuchs, Helmut; Hans, Wolfgang; Przemeck, Gerhard K H; Abe, Koichiro; Rathkolb, Birgit; Quintanilla-Martinez, Leticia; Hoelzlwimmer, Gabriele; Helfrich, Miep; Wolf, Eckhard; Ralston, Stuart H; de Angelis, Martin Hrabe.

In: PLoS Genetics, Vol. 4, No. 2, e7, 01.02.2008.

Research output: Contribution to journalArticle

Lisse, TS, Thiele, F, Fuchs, H, Hans, W, Przemeck, GKH, Abe, K, Rathkolb, B, Quintanilla-Martinez, L, Hoelzlwimmer, G, Helfrich, M, Wolf, E, Ralston, SH & de Angelis, MH 2008, 'ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta', PLoS Genetics, vol. 4, no. 2, e7. https://doi.org/10.1371/journal.pgen.0040007
Lisse TS, Thiele F, Fuchs H, Hans W, Przemeck GKH, Abe K et al. ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta. PLoS Genetics. 2008 Feb 1;4(2). e7. https://doi.org/10.1371/journal.pgen.0040007
Lisse, Thomas S ; Thiele, Frank ; Fuchs, Helmut ; Hans, Wolfgang ; Przemeck, Gerhard K H ; Abe, Koichiro ; Rathkolb, Birgit ; Quintanilla-Martinez, Leticia ; Hoelzlwimmer, Gabriele ; Helfrich, Miep ; Wolf, Eckhard ; Ralston, Stuart H ; de Angelis, Martin Hrabe. / ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta. In: PLoS Genetics. 2008 ; Vol. 4, No. 2.
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AU - Quintanilla-Martinez, Leticia

AU - Hoelzlwimmer, Gabriele

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AB - 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 pro alpha 1( 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.

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