Browsing by Subject "Osteogenesis Imperfecta"
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Item Craniofacial Morphology of Juvenile Mice with Osteogenesis Imperfecta(2020-05) Steele, Ashley T.; Menegaz, Rachel A.; Maddux, Scott D.; Kesterke, Matthew J.Osteogenesis Imperfecta (OI) is a heritable connective tissue disorder affecting the synthesis and structure of type I collagen (Col1) due to autosomal dominant mutations in proa1(I) or proa2(I) collagen genes (COL1A1 and COL1A2). Clinical manifestations of the severe OI type III include bone fragility, reduced physical stature, and midface hypoplasia resulting in a "triangle face" phenotype. Current treatment options have low-success rates and focus primarily on alleviating symptoms through surgical interventions and pharmacologic use of antiresorptive drugs. The homozygous OI murine (OIM-/-) mouse model has a nonlethal, recessively inherited mutation of the COL1A2 gene and exhibits adult cranial and post-cranial phenotypes similar to humans with severe OI type III; however, the juvenile phenotype is unknown. The goals of this study are: (1) to determine if significant differences in craniofacial skeletal shape and size are present at the age of weaning (21 days/4 weeks) in the OIM-/- mice compared to the wild type (WT) and (2) to determine if these differences are still significant when adjusted for the allometric effects of body size. OIM-/- and WT littermates were weaned at 21 days and scanned in-vivo with a Skyscan 1176 micro-CT system. Craniofacial geometric landmarks were collected using 3D Slicer software and were subsequently used to calculate interlandmark distances (ILDs) and centroid sizes. ILDs were scaled against skull/mandible centroid size to account for the effect of overall body size on shape analyses. Mann-Whitney U-tests were used to compare both absolute and relative (scaled) ILDs between the genotypes. Craniomandibular centroid sizes and absolute linear distances (skull, rostrum, palate, and mandible lengths) demonstrate that the OIM-/- mice are smaller overall than their WT littermates. When scaled to centroid size, juvenile OIM-/- mice have a decrease in nasal length, mandibular diastema length, and basicranium but an increase in cranial vaults, midface heights, and both maxillary and mandibular toothrow lengths compared to WT mice. For a given skull length, OIM-/- mice have shorter faces in both the anteroposterior and dorsoventral dimensions. The morphometric changes seen in the juvenile OIM-/- mice replicate the "triangle face" and relative macrocephaly that is commonly seen in human pediatric populations with OI. This suggests that this mouse model can potentially be used to investigate the structural changes underlying the human OI phenotype and for potential therapeutic interventions, such as biomechanical loading, myostatin knock-out, and pharmaceutical therapies. Additionally, the results of this study can be used to inform future investigations of Col1 in craniofacial development. Continuing to evaluate the etiology of this disorder can lead to better treatment options to improve the quality of life for patients with OI, especially pediatric patients.Item Dental Tissue Changes in Juvenile and Young Adult Mice with Osteogenesis Imperfecta(2022-05) Moore, Jacob C.; Handler, Emma; Menegaz, Rachel A.; Gonzales, Lauren A.Osteogenesis imperfecta (OI) encompasses a heterogeneous family of heritable connective tissue disorders characterized by insufficient or malformed type I collagen protein causing bone fragility, skeletal deformity, and significant dental issues. The most prominent oral characteristic of OI patients, dentinogenesis imperfecta (DI), is characterized by dentition with significant discoloration and structural defects. During normal dental development, specialized cells secrete layers of collagen-rich matrix, which are then mineralized to form the two hard tissues of the tooth – the enamel, the protective tissue that forms the crown of the tooth, and the dentin, which sits internal to the enamel and forms the bulk of the tooth. Importantly, the matrix on which dentin forms is primarily composed of type I collagen. In DI, the secretion of malformed type I collagen in the developing dentin matrix disrupts the normal regulation and organization of this process, causing issues such as hypomineralization, disorganized dentin tubule structure, and dentin hypertrophy. These abnormal structural properties result in the disease phenotype of DI, including discoloration, enamel attrition, and spontaneous dental fractures. This practicum aims to investigate the dental effects of OI by comparing mineralized dental tissue volumes of mice with a type I collagen mutation with wild-type mice with littermates at the juvenile and adult life stages. The animal model under study, the oim mouse (B6C3FE a/a-Col1a2OIM/J), produces abnormal type I collagen due to a mutation in the COL1A2 gene. Mice that are homozygous for this mutation demonstrate a severe OI phenotype, while heterozygotes demonstrate a mild OI phenotype. Prior studies demonstrate that adult oim mice have dental issues similar to those of humans with OI, including reduced dentin tubule density and dentin cross-sectional area. However, the effects of these mutations on dental tissues across the juvenile and young adult periods have not yet been characterized.Item Neurocranial Growth in the OIM Mouse Model of Osteogenesis Imperfecta(2022-05) Husain, Tooba S.; Menegaz, Rachel A.; Handler, Emma; Gonzales, Lauren A.Item Osteogenesis Imperfecta: An analysis of the inner ear development in Mus musculus (house mouse) with comments on hearing quality(2022-05) Huston, Lila A.; Gonzales, Lauren A.; Handler, Emma; Menegaz, Rachel A.; Millar, J. CameronOsteogenesis imperfecta (OI), a developmental disorder of type I collagen, is known to cause hearing loss in ~ 60% of the diseased population. Identified forms include conductive hearing loss (17.4% of OI patients), involving loss of function within the ossicular chain, and sensorineural hearing loss (25.8%), resulting from damage to the cochlea, with the most predominant form being mixed hearing loss (56.8%), involving damage to both the cochlea and ossicles. While OI-related pathologies have largely focused on the middle ear, the pathological appearance of the cochlea (the organ most often compromised in OI-related hearing loss) has gained little focus. In this study, we examine OI-related pathologies on the cochlea in a mouse model for the severe type III OI, to document 1) the morphological differences in the inner ear for adult wildtype mice compared to OI mice in order to determine the anatomy of the diseased state, and 2) intraindividual variation between cochlea of WT and OI mice to determine potential asymmetry in the etiology of the inner ear. We hypothesize that cochlea in mice with OI will have less consistent morphology overall than their WT counterparts due to abnormal growth of the bony capsule. 4 week and 16 week old OIM mice (B6C3Fe a/a-Col1a2oim/J) (n=25) were compared to unaffected wildtype (WT) littermates (n=29) with no known hearing defects. High-resolution micro-CT scans were created for all specimens and 3D models and volumes of the cochlea were generated using 3D Slicer software. Two-tailed Mann-Whitney U-tests were used to investigate differences between 1) right and left ears of the same mouse to examine intraindividual symmetry and 2) differences in volumes between WT and OI cochlea. No major morphologic differences between OI and WT were observed, except for minor areas of higher ossification at the base of the cochlea, mostly within the OI sample. Within WT specimens, we observed little intraindividual difference in the cochlear volume (0-3%). Within OI specimens, significant differences were observed in cochlear volume between right and left ears in the same animal, indicating potential unilateral effects (Mann-Whitney U, p<0.05). When average WT and OI volumes were compared, there was much overlap between the two samples although the OI volumes had a significantly larger range than the WT range (Mann-Whitney U, p=0.704 (w16), p=0.703 (w4)). Overall, our results indicate that mice with OI are much more likely to have evidence of unilateral cochlear volume losses, despite very little difference in overall shape appearance, possibly due to bony capsule encroachment. This find indicates an extremely high potential for sensorineural and mixed hearing loss in OI-bred mice and elucidates at least one mechanism behind how this type of hearing loss might be occurring. Little is known about the pathological appearance of the cochlea in OI, leading to difficulty in managing hearing loss. Further investigation of the etiology and progression of cochlear pathologies will allow for better outcomes in hearing for those patients afflicted with OI-related hearing loss.Item The Effect of Diet on Craniofacial Growth in Osteogenesis Imperfecta Mouse Model(2018-05) Ladd, Summer H.; Menegaz, Rachel A.; Maddux, Scott D.; Reeves, Rustin E.; Borejdo, JulianOsteogenesis imperfecta (OI, or "brittle bone disease") is a rare disorder that is caused by genetic point mutations (COL1A1/COL1A2) that affect type 1 collagen. In OI type III (severe) patients, limb bones are more susceptible to skeletal fractures and the bones of the craniofacial region are underdeveloped. Some OI type III patients also suffer from dental malocclusions or fractures (dentinogenesis imperfecta, DI). The goals of this project are 1) to describe the facial phenotype in an OI mouse model, to see if this model can be used to test potential behavioral and pharmaceutical interventions; and 2) to determine if diet and masticatory loading affect the development of the craniofacial region in the OI model. The homozygous OI murine (OIM-/-), a mouse strain with a nonlethal recessively inherited mutation of the COL1A2 gene, is a potential model for the human OI type III. OIM-/- and wild type (WT) littermates were raised from weaning (21 days) to adulthood (16 weeks). Digital 3D craniofacial landmarks were taken from in-vivo micro CT scans, and Kuskal-Wallis ANOVAs, along with Mann-Whitney tests, were used to compare centroid size and interlandmark distances among treatment groups. This practicum focuses on the Week 10 mice, with 3 treatment groups: OIMxM, WTxM, and WTxP. We acknowledge that the sample is incomplete due to factors beyond our immediate control, such as OIM-/- survivability. Adolescent OIM-/- mice (week 10) were found to have on average smaller cranial and mandibular centroid sizes compared to WT mice regardless of diet. Week 10 OIM-/- mice also show several morphological similarities to the OI type III human phenotype, such as shortened cranial vault height, shortened jaw length, and altered dental spacing secondary to a shortened tooth row. We conclude that the OIM mouse model shows potential for future investigations of the growth mechanisms underlying the craniofacial presentation of OI. Furthermore, preliminary results suggest that masticatory loading during the early growth period can be used to stimulate craniofacial bone growth and improve bone quality in the OIM mouse model. Future studies will continue to improve sample size by treatment and age groups. The significance of this project is that it will give a better understanding of the role of type 1 collagen and the biomechanical mechanics of craniofacial development, which are important in the search for a new treatment method in OI.