TY - JOUR
T1 - ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta
AU - Lisse, Thomas S
AU - Thiele, Frank
AU - Fuchs, Helmut
AU - Hans, Wolfgang
AU - Przemeck, Gerhard K H
AU - Abe, Koichiro
AU - Rathkolb, Birgit
AU - Quintanilla-Martinez, Leticia
AU - Hoelzlwimmer, Gabriele
AU - Helfrich, Miep
AU - Wolf, Eckhard
AU - Ralston, Stuart H
AU - de Angelis, Martin Hrabe
PY - 2008/2/1
Y1 - 2008/2/1
N2 - 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.
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.
KW - carboxyl-terminal propeptide
KW - endoplasmic-reticulum stress
KW - I collagen
KW - differential expression
KW - bone histomorphometry
KW - pro-ALPHA-1(I) chain
KW - transgenic mice
KW - binding sites
KW - murine model
KW - lethal
U2 - 10.1371/journal.pgen.0040007
DO - 10.1371/journal.pgen.0040007
M3 - Article
SN - 1553-7390
VL - 4
JO - PLoS Genetics
JF - PLoS Genetics
IS - 2
M1 - e7
ER -