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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.; Hrabé de Angelis, Martin (February 2008): ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta.
In: PLOS Genetics 4(2) , pp. 1-11


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.