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ER Stress-Mediated Apoptosis in a New Mouse Model of Osteogenesis imperfecta

2008; Public Library of Science; Volume: 4; Issue: 2 Linguagem: Inglês

10.1371/journal.pgen.0040007

1553-7404

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,

Wnt/β-catenin signaling in development and cancer

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 proα1(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.