Morphological variability in the inner ear of mice with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is known to cause hearing loss in ~60% of the affected human population. While OI-related pathologies have been studied in the middle ear, the development of cochlear pathologies is less well understood. In this study, we examine OI-related pathologies of the cochlea in a mouse model of OI to (1) document variation between OI and unaffected mice, and (2) assess the intrusion of the otic capsule onto the cochlea by analyzing differences in duct volumes. Juvenile and adult OIM C57BL/6mice were compared to unaffected wildtype (WT) mice using three-dimensional models of the cochlea generated from high resolution micro-CT scans. Two-tailed Mann-Whitney U tests were then used to investigate duct volume differences both within and between the OI and WT samples. Areas of higher ossification were observed at the cochlear base in the OI sample. OI mice also had significant intraindividual differences in duct volume between right and left ears (4%-15%), an effect not observed in WT mice. WT and OI duct volumes showed a large degree of overlap, although the OIM volumes were more variable. Our findings indicate that OIM mice are likely to exhibit more asymmetry and variation in cochlear volume despite minor differences in sample cochlear volumes, possibly due to bony capsule intrusion. This suggests a potential mechanism of hearing loss, and a high potential for cochlear and otic capsule alteration in OIM mice.

Dental tissue changes in juvenile and adult mice with osteogenesis imperfecta.

Osteogenesis imperfecta (OI), a disorder of type I collagen, causes skeletal deformities as well as defects in dental tissues, which lead to increased enamel wear and smaller teeth with shorter roots. Mice with OI exhibit similar microstructural dentin changes, including reduced dentin tubule density and dentin cross-sectional area. However, the effects of these mutations on gross dental morphology and dental tissue volumes have never been characterized in the osteogenesis imperfecta murine (OIM) mouse model. Here we compare mineralized dental tissue measurements of OIM mice and unaffected wild type (WT) littermates at the juvenile and adult stages. The maxillary and mandibular incisors and first molars were isolated from microCT scans, and tissue volumes and root length were measured. OIM mice have smaller teeth with shorter roots relative to WT controls. Maxillary incisor volumes differed significantly between OIM and WT mice at both the juvenile and young adult stage, perhaps due to shortening of the maxilla itself in OIM mice. Additionally, adult OIM mice have significantly less crown enamel volume than do juveniles, potentially due to loss through wear. Thus, OIM mice demonstrate a dental phenotype similar to humans with OI, with decreased tooth size, decreased root length, and accelerated enamel wear. Further investigation of dental development in the OIM mouse may have important implications for the development and treatment of dental issues in OI patients.

Neurocranial growth in the OIM mouse model of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a disorder of type I collagen characterized by abnormal bone formation. The OI craniofacial phenotype includes midfacial underdevelopment, as well as neurocranial changes (e.g., macrocephaly and platybasia) that may also affect underlying nervous tissues. This study aims to better understand how OI affects the integrated development of the neurocranium and the brain. Juvenile and adult mice with OI (OIM) and unaffected wild type (WT) littermates were imaged using in vivo micro-computed tomography (microCT). Virtual endocast models were used to measure brain volume, and 3D landmarks were collected from the cranium and brain endocasts. Geometric morphometric analyses were used to compare brain shape and integration between the genotypes. OIM mice had increased brain volumes (relative to cranial centroid size) only at the juvenile stage. No significant difference was seen in cranial base angle (CBA) between OIM and WT mice. However, CBA was higher in juvenile than in adult OIM mice. Brain shape was significantly different between OIM and WT mice at both stages, with OIM mice having more globular brains than WT mice. Neurocranial and brain morphology were strongly integrated within both genotypes, while adult OIM mice tended to have lower levels of skull-brain integration than WT mice. These results suggest that neurocranial dysmorphologies in OI may be more severe at earlier stages of postnatal development. Decreased skull-brain integration in adult mice suggests that compensatory mechanisms may exist during postnatal growth to maintain neurological function despite significant changes in neurocranial morphology.