Browsing by Author "McBride, Alexandra H."
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Item Absolute and Relative Morphometric Differences in the Craniofacial Skeleton of OIM-/- Mice and Wild-Type Littermates(2019-03-05) McBride, Alexandra H.; Organ, Jason; Menegaz, Rachel A.; Ladd, SummerPurpose: Osteogenesis Imperfecta (OI, or “Brittle Bone Disease”) is a disorder caused by genetic point mutations in COL1A1/COL1A2 which affect the synthesis of type I collagen (Col1). Humans with the severe type III OI exhibit increased susceptibility to skeletal fractures and shortened stature, as well as cranial dysmorphologies and dental malocclusions. Mouse models of Col1 defects report postcranial phenotypes similar to those seen in humans, with a limited number of studies reporting alterations to cranial and dental integrity. This project tests the hypothesis that the reduced craniofacial dimensions reported in both humans and mice with Col1 defects are linked to an overall reduction in body size. Methods: The homozygous OI murine (OIM-/-) is a mouse strain with a nonlethal recessively inherited mutation of the COL1A2 gene. Wild-type (WT) and OIM-/- littermates were weaned at 21d and raised until adult (16 weeks). 3D morphometric landmarks were collected from serial in-vivo µCT scans at 4, 10, and 16 weeks using etdips software. Past 2.17 software was used to Procrustes-transform (rotate and translate) the landmark data, and to calculate interlandmark distances (ILDs) and centroid sizes. ILDs were scaled against skull/mandible centroid size and skull/mandible length to account for the effect of size. Mann-Whitney U tests (α=0.05) were used to compare centroid sizes and both absolute and relative (scaled) ILDs between the genotypes. Results: When comparing absolute morphometric distances, adult OIM-/- mice have shorter skulls, basicrania, palates, mandibles, and toothrows. However, OIM-/-mice are smaller overall than their WT littermates as measured by both body mass and craniomandibular centroid sizes. When the effects of size are accounted for, the trend for interlandmark distances in WT mice to be greater than those in OIM-/- mice is significantly reduced or even reversed. For example, when scaled to centroid size, no significant difference exists between WT and OIM-/- mice in skull, basicranial, or mandibular length. OIM-/- mice have a relatively short midface, short nasal bones, tall mandibular corpora and long mandibular toothrows. Conclusions: These findings underscore the importance of size and scaling in morphometric analyses. The deleterious effect of Col1 mutations on global skeletal dimensions, in combination with localized morphometric changes, may underlie the facial phenotype seen in human patients with OI type III. Attempts to identify these localized changes should first account for the restricted growth and small body sizes present in individuals with OI.Item Craniofacial Bone Mineral Density During Growth in Mice with Osteogenesis Imperfecta (OI)(2021) Miller, Courtney; Wright, Tommy; McBride, Alexandra H.; Organ, Jason; Menegaz, Rachel A.Purpose: Osteogenesis imperfecta(OI) is a genetic connective tissue defect resulting in fragile bones due to mutations affecting formation of type I collagen. Low bone mineral density (BMD) in the post-cranial skeleton has been reported in human patients and murine models with OI, yet little is known about craniofacial biomineralization in the disorder. Typically, skeletal mineralization is responsive to the strain environment. The aim of this study is to investigate longitudinal changes in craniofacial BMD in a mouse model of OI type III (most severe form), and to quantify BMD in regions relative to feeding biomechanical forces. Methods: Homozygous recessive OI murine (OIM), a mouse strain with a COL1A2 mutation modeling OI type III, and unaffected wild-type (WT) littermates were micro-CT scanned at weeks 4, 10, and 16. BMD in eight regions was analyzed using Bruker CTAnalyzer software and Mann-Whitney U tests. Results: OIM mice had significantly (p< 0.05) lower BMD than WT mice in all eight regions during week 4, no significant differences in week 10, and significant differences at the parietal bone, mandibular symphysis, and maxillary incisor regions during week 16. Absolute BMD was higher within regions proximal to the bite point at skeletal maturity. Conclusions: These results support a trend that OIM mice have lower BMD in the craniofacial skeleton compared to WT mice throughout growth and BDM in all mice is affected by proximity to bite forces. Understanding craniofacial mineralization patterns in OI could assist in the implementation of pharmaceutical interventions to increase BMD.Item 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.Item Craniofacial Bone Mineral Density in Mice with Osteogenesis Imperfecta (OI)(2019-03-05) Ladd, Summer; Organ, Jason; Menegaz, Rachel A.; McBride, Alexandra H.Purpose: Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by the abnormal synthesis and assembly of type I collagen (Col1), 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 Col1 defects, as seen in OI type III, affect BMD within the craniofacial skeleton; (2) to examine whether craniofacial BMD covaries with diet-related biomechanical loading. Methods: 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-hard (n=6), OIM-soft (n=3), WT-hard (n=9), and WT-soft (n=3). 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 treatments (α = 0.05). Results: At all ROIs except for the frontal bone, WT-hard mice had significantly (p p = 0.052) with the current sample sizes. Similarly, at the mandibular and cranial vault ROIs, WT-soft mice tended to have higher BMD than OIM-hard and/or OIM-soft mice (p Conclusions: These results suggest that craniofacial BMD is generally lower in individuals with Col1 defects, consistent with the postcranial presentation. WT mice raised on a hard diet were observed to have the highest BMD measurements across the craniofacial skeleton, however no significant differences were observed between OIM-/- mice raised on hard versus soft diets. While diet-associated loading may influence craniofacial BMD, in this study Col1 status appears to be the primary determinant of BMD.