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

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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 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. Osteogenesis imperfecta (OI) is a heterogeneous collection of connective tissue disorders typically caused by mutations in the COL1A1/2 genes that encode the chains of type I collagen, the principle structural protein of bone. Phenotypic expression in OI depends on the nature of the mutation, causing a clinical heterogeneity ranging from a mild risk of fractures to perinatal lethality. Here, we describe a new OI mouse model with a dominant mutation in the terminal C-propeptide domain of Col1a1 generated using the N-ethyl-N-nitrosourea (ENU) mutagenesis strategy. Heterozygous animals developed severe-to-lethal phenotypes that were associated with endoplasmic reticulum stress, and caspases-12 and −3 activation within calvarial osteoblasts. We provide evidence for endoplasmic reticulum stress–associated apoptosis as a key component in the pathogenesis of disease.