title: ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta.
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 proalpha1(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.
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Lisse
authors.forename: Frank
authors.initials: F
authors.lastname: Thiele
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.forename: Gerhard K H
authors.initials: GK
authors.lastname: Przemeck
authors.forename: Koichiro
authors.initials: K
authors.lastname: Abe
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.forename: Gabriele
authors.initials: G
authors.lastname: Hoelzlwimmer
authors.forename: Miep
authors.initials: M
authors.lastname: Helfrich
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabé de Angelis
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation; D005804:Genes, Lethal; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011247:Pregnancy
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D004247:DNA