Dataset Information

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.

SUBMITTER: Lisse TS

PROVIDER: S-EPMC2222924 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta.

Lisse Thomas S TS Thiele Frank F Fuchs Helmut H Hans Wolfgang W Przemeck Gerhard K H GK Abe Koichiro K Rathkolb Birgit B Quintanilla-Martinez Leticia L Hoelzlwimmer Gabriele G Helfrich Miep M Wolf Eckhard E Ralston Stuart H SH Hrabé de Angelis Martin M

PLoS genetics 20080201 2

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 mappe ...[more]

PMID: 18248096

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Project description:Osteogenesis imperfecta (OI) is a fairly common generalized connective disorder characterized by low bone mass, bone deformities and impaired bone quality that predisposes affected individuals to musculoskeletal fragility. Periodontal ligament (PDL)-alveolar bone and PDL-cementum entheses' roles under OI conditions during physiological loading and orthodontic forces remain largely unknown. In addition, bisphosphonates (e.g., alendronate) are commonly used therapeutics for the treatment of OI. Our knowledge, in terms of the affects of alendronate treatment on the PDL entheses in OI is also far from complete. In this study, we identified craniofacial skeletal defects in an osteogenesis imperfecta (oim) murine model of OI. Relative to wild-type littermates, oim mice were found to have decreased skull length, cranial height/width/length, nose length, nasal length, and frontal length. Next, we discovered that oim mice exhibited defects in several dental structures, including short roots and decreased volumes of the alveolar bone, dentin, and cellular cementum. Further, we specifically investigated periodontal defects in the oim mice. Alveolar bone loss in oim mice was primarily associated with elevated bone resorption due to an increased osteoclast number, along with reduced bone formation related to increased sclerostin (SOST) expression. PDL fibers in oim mice were disrupted and discontinuous, while Sharpey's fibers at the PDL-bone entheses were reduced. Mechanism-based studies showed that catabolism of the PDL was elevated in oim mice, as revealed by an increase in MMP13 and CTSK expression. Meanwhile, the quality of the collagen fibers were impaired in oim mice due to a large accumulation of uncleaved collagen I fibers. With alendronate treatment, however, we could partially rescue these phenotypes. This study, for the first time, characterized periodontal defects in oim mice, detailed craniofacial defects and demonstrated the effectiveness of alendronate in partially restoring these defects.

Dataset Information

ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta.

Publications

ER stress-mediated apoptosis in a new mouse model of osteogenesis imperfecta.

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