Transgenic mouse model of the mild dominant form of osteogenesis imperfecta.

Abstract

Osteogenesis imperfecta type I Is a mild, dominantly inherited, connective tissue disorder characterized by bone fragility. Mutations in type I collagen account for all known cases. In Mov-13 mice, integration of a murine retrovirus within the first Intron of the al(I) collagen gene results in a null allele blocked at the level of transcription. This study demonstrates that mutant mice heterozygous for the null allele are a model of osteogenesis Imperfecta type I. A defect in type I collagen production is associated with dominant-acting morphological and functional defects in mineralized and nonmineralized connective tissue and with progressive hearing loss. The model provides an opportunity to investigate the effect of a reduced amount of type I collagen on the structure and integrity of extracellular matrix. It also may represent a system in which therapeutic strategies to strengthen connective tissue can be developed.The Mov-13 strain was generated by exposing mouse embryos to Moloney murine leukemia virus. Genetic and molecular evidence indicated that a single copy of the provirus integrated into the first intron of the al(I) collagen gene (13,14). The proviral insert is associated with a change in chromatin conformation and de novo methylation ofthe gene, and it prevents initiation of transcription (15-17). Mice homozygous for the null mutation die in utero because of failure of the vascular system (18). However, heterozygous Mov-13 mice (referred to in this paper simply as Mov-13 mice) do not display an obvious mutant phenotype. Given the nature of the mutation harbored by Mov-13 mice, it was hypothesized that they would serve as a model of 01-I. In the present report we have undertaken a detailed biochemical and functional analysis of Mov-13 mice to determine if this were the case.Osteogenesis imperfecta type I (O0-I) is a mild disorder characterized by bone fracture without deformity, blue sclerae, normal or near normal stature, and autosomal dominant inheritance (1, 2). The incidence is estimated to be 1 of 20,000 live births, and males and females are affected equally. Osteopenia is associated with an increased rate of long-bone fracture upon ambulation. For reasons not well understood, fracture frequency decreases dramatically at puberty and during young adult life but increases once again in late middle age (3). Progressive hearing loss, often beginning in the second or third decade, is a feature of this disease in about half of the families (4). The proportion of O0-I patients with significant hearing loss rises steadily into middle age despite the general decline in fracture frequency. Conductive or mixed (conductive and sensorineural) hearing loss is more common in dominant OI than sensorineural hearing loss alone. Dentinogenesis imperfecta is observed in a small subset of the patient population (5).All O0-I cases to date have been associated with mutations in the extracellular matrix molecule type I collagen (6). There is evidence that both null alleles and structural mutations can produc...

Role of genetic background in determining phenotypic severity throughout postnatal development and at peak bone mass in Col1a2 deficient mice (oim)

“…The Brtl model is a glycine to cysteine substitution in the α1(I) chain leading to an OI type IV-like phenotype [45]. The Mov-13 model is a transgenic model carrying a murine retrovirus in the first intron of the COL1A1 gene resulting in a null allele and an OI type I-like phenotype [46]. Femurs from Brtl mice had reduced maximum load compared to Wt at three months of age [25].…”

Effect of Mechanical Loading On Periodontal Cells

“…During the past decade, transgenic animal models have been introduced into the research of bone biology (Pavlin et al, 1989(Pavlin et al, , 1992Bonadio et al, 1990;Kream et al, 1995;Ducy et al, 1996;Rossert et al, 1996), but their utilization for studying the regulation of periodontal cells and the alveolar bone homeostasis was limited. A recently developed tooth movement model in wild-type and transgenic mice (Pavlin et al, 2000a(Pavlin et al, ,b, 2001a allows for the study of genetic responses in individual cell populations within the periodontal ligament and the alveolar bone perturbed by mechanical stress in a non-invasive manner.…”

“…Furthermore, these results, and those of others, emphasize the necessity for results obtained from bone cells in culture to be confirmed in an in vivo model, whenever possible. Several transgenic models have been used to study osteoblast biology (Bonadio et al, 1990;Ducy et al, 1996;Rossert et al, 1996), but this technique has not been applied in studies investigating either the effect of mechanical loading on bone cells or the mechanical response of the dentoalveolar complex to physiological forces or to orthodontic stress. To address this deficiency, and to utilize the advantages of a smaller animal model, we developed a biomechanically defined animal model for periodontal mechanical loading and a relative quantitative video image analysis for measuring the degree of expression of osteoblast marker genes in periodontal osteoblasts.…”

In vivo cellular adaptation to ER stress: survival strategies with double-edged consequences

“…For mutations that affect the folding or secretion of collagen I and II, the relative contribution of ER stress to the disease outcome is difficult to assess because of the developmental requirement for these proteins and their roles as structural components of the ECM. For example, mice heterozygous for either a Col1a1-or Col2a1-null allele develop skeletal defects (Lohler et al, 1984;Harbers et al, 1984;Bonadio et al, 1990; Li et al, 1995;Sahlman et al, 2001) and, therefore, loss of collagen function is an integral part of the pathogenesis observed. By contrast, the effects of null mutations of Comp, Col10a1 and Matn3 in mice are subtle (Rosati et al, 1994; Kwan et al, 1997;Svensson et al, 2002;Ko et al, 2004;van der Weyden et al, 2006), facilitating evaluation of the impact of ER stress in skeletal dysplasia.…”