Browsing by Subject "osteogenesis imperfecta"

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Craniofacial Bone Mineral Density in Mice with Osteogenesis Imperfecta
(2019-05) McBride, Alexandra H.; Menegaz, Rachel A.; Muchlinski, Magdalena N.; Maddux, Scott D.
Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by the abnormal synthesis and assembly of type I collagen, a major organic component of bone. Clinical manifestations of the severe OI type III include small body size, limb deformities, and low bone mineral density (BMD) within the post-cranial skeleton. OI type III often co-occurs with craniofacial defects, such as dentinogenesis imperfecta (DI). The goals of this study are: (1) to examine whether type I collagen defects, as seen in OI type III, affect BMD within the craniofacial skeleton; (2) to determine whether BMD varies among specific region of the craniofacial skeleton; (3) to examine whether diet-related variation in biomechanical loading is related to higher craniofacial BMD. The homozygous recessive murine mouse (OIM-/-) is a model for OI Type III. Similar to human OI patients, OIM-/- mice exhibit low post-cranial BMD, smaller body size, and DI. OIM-/- mice and WT littermates were weaned at 21 days and raised on either hard (high loading) or soft (low loading) diets. This resulted in four genotype x diet treatment groups: OIM-soft (n=3), OIM-hard (n=6), WT-soft (n=3), and WT-hard (n=9). Micro-CT scans were collected at 16 weeks (skeletal maturity). BMD was measured using Bruker CTAnalyzer software for eight regions of interest (ROIs) within the mandible (TMJ, corpus at the second molar, and symphysis), facial skeleton (nasal bone, maxilla at the second molar, premaxilla at the incisor), and cranial vault (frontal and parietal bones). Pairwise Mann-Whitney U tests were used to statistically compare BMD between genotypes (α = 0.100). When controlling for diet, WT mice had significantly greater BMD values than OIM mice at each ROI except at the maxilla at M2. Although variation between treatment groups, a general trend for increased BMD in "high" strain regions, such as the mandibular symphysis or the maxillary incisor, existed. Lastly, WT mice raised on a hard diet were observed to have the highest BMD measurements across each region the craniofacial skeleton, however no significant differences were observed between OIM-/- mice raised on hard versus soft diets. These results suggest that craniofacial BMD is generally lower in individuals with type I collagen defects, consistent with the post-cranial presentation. Additionally, regions associated with high strain during routine masticatory loading exhibited increased BMD as compared to regions of the skull that experience relatively "low" strain during chewing. While diet-associated loading may influence craniofacial BMD, in this study type I collagen status appears to be the primary determinant of BMD.
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.
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, Julian
Osteogenesis 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.