Browsing by Author "Menegaz, Rachel A."
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Item A review of musculoskeletal adaptations in individuals following major lower-limb amputation(Hylonome Publications, 2022-06-01) Finco, M. G.; Kim, Suhhyun; Ngo, Wayne; Menegaz, Rachel A.Structural musculoskeletal adaptations following amputation, such as bone mineral density (BMD) or muscle architecture, are often overlooked despite their established contributions to gait rehabilitation and the development of adverse secondary physical conditions. The purpose of this review is to provide a summary of the existing literature investigating musculoskeletal adaptations in individuals with major lower-limb amputations to inform clinical practice and provide directions for future research. Google Scholar, PubMed, and Scopus were searched for original peer-reviewed studies that included individuals with transtibial or transfemoral amputations. Summary data of twenty-seven articles indicated reduced BMD and increased muscle atrophy in amputees compared to controls, and in the amputated limb compared to intact and control limbs. Specifically, BMD was reduced in T-scores and Z-scores, femoral neck, and proximal tibia. Muscle atrophy was evidenced by decreased thigh cross-sectional area, decreased quadriceps thickness, and increased amounts of thigh fat. Overall, amputees have impaired musculoskeletal health. Future studies should include dysvascular etiologies to address their effects on musculoskeletal health and functional mobility. Moreover, clinicians can use these findings to screen increased risks of adverse sequelae such as fractures, osteopenia/porosis, and muscular atrophy, as well as target specific rehabilitation exercises to reduce these risks.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 Additive Effects of Diabetes and Lower-Limb Amputation on Osteoarthritis with Comparison to Diabetic and Healthy Controls(2022) Ngo, Wayne; Finnerty, Cait; Finco, MG; Holley, Bethany; Menegaz, Rachel A.Purpose: Individuals with type II diabetes and individuals with lower-limb amputation each have increased risks of developing osteoarthritis compared to the general population. Despite the high co-occurrence of type II diabetes with lower-limb amputations, the additive effects of these conditions are unclear. In order to better manage the risk of developing osteoarthritis in these populations, a better understanding of how diabetes and amputation might compound osteoarthritis risk is needed. Methods: We measured hip and knee joint space, as indicators of osteoarthritis, in four groups of individuals: 1) lower-limb amputees with diabetes, 2) lower-limb amputees without diabetes 3) diabetic controls, and 4) healthy controls. We hypothesized lower-limb amputees with diabetes would have the most impaired musculoskeletal health, followed by amputees without diabetes, diabetic controls, then healthy controls. 30 total CT scans of males (42-79 years; BMI 19.7 - 48.9 kg/m2) were obtained from the New Mexico Decedent Image Database. 10 scans were identified for amputees, diabetic controls, and healthy controls. Half of the lower-limb amputees had diabetes while half did not, to differentiate effects of diabetes and amputation on musculoskeletal health. 3D Slicer software was used to measure hip and knee joint spaces as indicators of osteoarthritis. Comparisons between groups were assessed using Kruskal-Wallis with Dunn's post hoc tests. Results: Amputees with and without diabetes showed significantly narrower hip (p=0.01) and knee (p=0.08) joint space bilaterally compared to diabetic and healthy controls. This result suggests amputees could be at a higher risk of developing lower-limb osteoarthritis compared to diabetic and healthy individuals, which is in line with prior work demonstrating the prevalence of osteoarthritis in the amputee population. Conclusions: In agreement with our hypothesis, box plots showed trends of amputees with diabetes having the most narrowed joint space, followed by amputees without diabetes, then diabetic controls, and healthy controls. While not statistically significant, these trends suggest amputees with diabetes are at increased risk of developing osteoarthritis compared to amputees without diabetes. Perhaps the aggressive management of blood glucose and post-amputation physiotherapy treatments could help reduce joint deterioration in these patients. Future work will focus on increasing sample size to assess if these findings are generalizable to a larger population. Increased risks of osteoarthritis can lead to pain, limited mobility, and decreased quality of life. This study can potentially inform clinical standards of care for patients with amputations. Earlier interventions such as proactive musculoskeletal screenings and targeted exercises may reduce risks of developing osteoarthritis, leading to improved clinical outcomes.Item Assessing Ecogeographical Variation in the Nasal Passages Utilizing 3D Semilandmarks(2021-05) Ward, Lyndee A.; Maddux, Scott D.; Menegaz, Rachel A.; Handler, EmmaPrior research has shown strong statistical relationships between geographically-patterned variation in nasal skeletal morphology and global climatic conditions. Specifically, the nasal skeletons of individuals indigenous to cold-dry environments tend to be longer, taller, and especially narrower, than those from hot-humid environments. As the nasal passages heat and humidify inspired air for entry into the lungs, this morphological patterning is believed to reflect the specific air-conditioning demands of different climates. However, while it is widely assumed the morphology of the nasal skeleton accurately reflects that of the functional (soft-tissue) nasal passages, the existence of ecogeographic variation in the three-dimensional (3D) nasal soft tissues has yet to be empirically demonstrated. This study investigates 3D shape variation in decongested soft-tissue nasal passages of individuals ancestrally derived from cold-dry (CD) and hot-humid (HH) environments (n=20). Using 3D Slicer and Avizo, a total of 260 semilandmarks were collected from the decongested nasal passages of Each individual. General Procrustes Analysis (GPA) was then used to align the semilandmark configurations of all 20 individuals and a Principal Component Analysis (PCA) was subsequently performed using the Geomorph package in R. Our results indicate PC1 (19.13%) largely contrasts CD individuals with positive PC1 scores (relatively narrower nasal passages) from HH individuals with negative PC1 scores (relatively wider nasal passages). These results generally conform to morphological expectations, suggesting a general concordance between skeletal and decongested soft-tissue nasal anatomy. This study thus provides the impetus for future research investigating the relationship between ecogeographic variation in nasal soft-tissue anatomy and air-conditioning physiology.Item Contrast-enhanced micro-CT approaches for visualizing musculoskeletal development in neonatal mice(2023) Stalls, Javan; Miller, Courtney; Gonzales, Lauren; Lesciotto, Kate; Handler, Emma; Organ, Jason; Menegaz, Rachel A.Contrast-enhanced micro-CT approaches for visualizing musculoskeletal development in neonatal mice Javan A. Stalls, Courtney A. Miller, Jason M. Organ, Emma K. Handler, Lauren A. Gonzales, Kate M. Lesciotto, Rachel A. Menegaz Purpose: While there are many forms of radiological imaging that can be used to gather anatomical data from biological specimens, computed tomography (CT) imaging has been the gold standard for visualizing dense tissue, such as bone, with detailed resolution. However, this imaging modality is not well suited for soft tissues (muscle, brain, abdominal organs, cartilage, etc.) due to their decreased tissue density. The inability to distinguish between soft tissues in CT scans limits our ability to investigate the bone-muscle interactions known to stimulate and direct bone modeling during early postnatal development. The development of contrast-enhancing staining agents, capable of binding materials to increase their radiodensity, has allowed for more accurate and enhanced visualizations of less dense soft tissues, such as muscle and brain structures. Contrast agents such as iodine have differential affinities for the different soft tissues in the body allowing for easier visualization and segmentation of soft tissues in relation to the skeleton. Previous studies have used contrast-enhanced CT (CE-CT) scanning to analyze early development of mice from prenatal stages to postnatal day 7. However, additional CE-CT imaging during the first three postnatal weeks is needed to understand muscle-bone interactions during critical periods of behavioral development, such as suckling and weaning. The goal of this project is to develop a CE-CT protocol and corresponding anatomical atlas showing the development of skeletal and soft tissue structures in the crania of neonatal mice from birth to weaning. Methods: Neonatal and preweaning mice (B6C3Fe a/a-Col1a2OIM/J) were euthanized on day of birth (P0), postnatal day 7 (P7), and postnatal day 14 (P14). Ethanol-fixed tissues were submerged in 1.25% iodine in 70% ethanol (I2E) for 2-14 days, with the skin intact in order to preserve cutaneous musculature. Both pre-stained and post-stained tissues were scanned using a MRS CT-80 micro-CT machine (20 µm3 voxel resolution). Results: Preliminary CE-CT scans following 10 days in an iodine stain present improved visualization of soft tissue (brain structures, cranial muscles, salivary glands) when compared to the baseline bone CT scans. Conclusion: These scans will be used to develop 3D models of musculoskeletal ontogeny from birth-weaning, providing insights into this critical developmental period. The use of CT contrast agents such as iodine offers new opportunities to investigate the anatomical interactions of bone and muscle during early development, and can be applied to investigate models of both normal growth and pathological disorders affecting musculoskeletal growth.Item Cranial Bone Ossification Trajectories in a Mouse Model of Osteogenesis Imperfecta(2023) Miller, Courtney; Lugo, Laura; Husain, Tooba S.; Organ, Jason; Handler, Emma; Gonzales, Lauren; Menegaz, Rachel A.Purpose: Osteogenesis imperfecta (OI) is a genetic disorder that affects the production of type I collagen. Altered collagen production results in delayed or impaired skeletal formation and biomineralization. It also results in the defining characteristics of OI: brittle bones and high rates of fractures. Investigations of skeletal growth in OI have primarily focused on the postcranial skeleton, where interrupted, atypical, and disorganized ossification is seen at long bone growth plates. However, few studies have investigated changes in craniofacial growth in OI and there are currently few early interventions to improve growth trajectories in this region. The current medication prescribed for children with OI to improve skeletal growth, such as bisphosphonates, have major side effects and are not suitable for long-term use. A better understanding of craniofacial development in OI can help with targeting specific developmental stages when new treatments can be administered to provide the best results. The aim of this study is to examine cranial ossification from birth to weaning to determine where and when differences in growth occur in OI. We hypothesize that starting at birth mice with OI will have delayed craniofacial growth due to the poor collagen formation. Methods: To test our hypothesis, we collected cranial bone volumes from micro-CT scans of the homozygous recessive OI murine model (OIM or B6C3Fe a/a-Col1a2oim/oim) and compared them to their wild type (WT) littermates. The OIM model has a COL1A2 mutation that has been found to express a similar skeletal phenotype to the severe form (type III) of OI in humans. Bone volumes were collected from birth (P0) and weaning (P21) from the nasal, frontal, parietal, interparietal, and occipital bones (n=2/genotype/timepoint). Results: At birth, OIM and WT bone volumes were similar. By weaning, bone volume was lower in OIM mice compared to WT mice. Our results demonstrate that OIM mice have reduced rates of bone ossification between birth and weaning, and these differences are most profound in the facial and occipital regions. Additionally, OIM skulls are characterized by low bone volume and potential delays in the closure of cranial sutures and fontanelles. Conclusions: This study suggests that the divergence in cranial ossification rates related to COL1A2 mutations occurs postnatally. Interventions to recover craniofacial bone growth in this experimental model should focus on the critical growth period between birth and weaning. Results from this research have the potential to assist in developing treatments and highlight the importance of early life development of the craniofacial bones in human patients 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.Item Craniofacial Morphology of Juvenile Mice with Osteogenesis Imperfecta(2020) Menegaz, Rachel A.; Organ, Jason; Steele, Ashley T.Osteogenesis imperfecta (OI) type III is a severe genetic disorder of type I collagen (Col1) which results in bone fragility, reduced stature, and impaired craniofacial growth. To investigate the mechanisms by which Col1 mutations alter craniofacial growth, we used the homozygous recessive OI murine (OIM) mouse model, which is known to exhibit human-like adult phenotypes but for which the juvenile phenotype is unknown. Weaning OIM and wild type (WT) littermates were µCT scanned at 21 days. Craniofacial landmarks were collected using 3D Slicer software. Interlandmark distances (ILDs) and centroid sizes were calculated using Past 2.17 software. ILDs were scaled against skull/mandible centroid size to remove the effect of overall body size for shape analyses. Mann-Whitney U-tests were used to compare absolute and relative (scaled) ILDs between genotypes. Craniomandibular centroid sizes and absolute linear distances (skull, rostrum, palate, and mandible lengths) demonstrate that OIM mice are smaller overall compared to WT littermates. When scaled to centroid size, juvenile OIM mice have a decrease in midface height, nasal and mandibular diastema length but increased hemimandible length 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 juvenile OIM mice replicate the midfacial hypoplasia seen in human children with OI. This mouse model can be used to investigate the structural changes underlying the human OI phenotype and potential therapeutic interventions. These results can be used to inform future investigations of Col1 in craniofacial development.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 Development of Craniofacial Biomineralization in Mice with Osteogenesis Imperfecta (OI)(2020) Menegaz, Rachel A.; Robert Wright, TommyOsteogenesis Imperfecta (OI) is a rare autosomal dominant disorder characterized by genetic mutations that affect type I collagen (Col1) synthesis. The severe OI type III phenotype generally includes a short stature, low bone mineral density (BMD), dental problems, hearing loss, and blue sclerae. In this study, we use a mouse model of OI type III to examine how mutations in type I collagen synthesis impact craniofacial biomineralization during postnatal growth. The homozygous recessive osteogenesis imperfecta murine (OIM) is characterized by increased skeletal fractures, low postcranial BMD, progressive skeletal deformities, and small body size. Wild type mice (WT) and OIM littermates (n>3/genotype) were micro-CT scanned at weaning (4 weeks) and adulthood (16 weeks). BMD at three regions of interest (ROI) within the mouse skull was measured using Bruker CTAnalyzer software: (1) the temporomandibular joint (TMJ), (2) the parietal bone (1mm from the sagittal suture), and (3) the anterior maxilla at the incisal alveolus. Mann-Whitney U-tests (?=0.05) were used to compare BMD values between the genotypes for each ROI. At weaning, OIM mice had significantly lower BMD values (g.cm-3 CaHA) than their wild type littermates at all three ROIs, and these differences persist into adulthood. This decrease in BMD reflects decreased deposition of CaHA due to an abnormal collagen framework in the craniofacial skeleton of OIM mice. Ongoing efforts will expand this analysis to quantify the development of BMD at additional regions within the craniofacial skeleton.Item Effects of Osteogenesis Imperfecta on Dental Tissue Volumes in Mice(2022) Moore, Jacob; Handler, Emma; Menegaz, Rachel A.; Gonzales, Lauren; Organ, JasonOsteogenesis imperfecta (OI), commonly known as brittle bone disease, is associated with lifelong dental problems, including increased dental fractures, discolored teeth, and malocclusion. OI is a disorder of the type I collagen protein. Insufficient amounts or misshapen forms of this protein lead to disruptions in the microstructure of bone and teeth tissues. Dentin, the hard tissue which comprises the bulk of the tooth and absorbs shock forces during chewing, develops on a type I collagen matrix. Thus, collagen abnormalities in OI lead to disorganized and less stable dentin. Further, teeth in people with OI frequently exhibit dentin hypertrophy, where increased amounts of dentin are deposited at the interior of the tooth, shortly after dental eruption. Enamel, unlike dentin, develops on a matrix of non-collagenous proteins, and is thought to develop normally in OI. However, abnormalities in the underlying dentin in OI can lead to enamel fractures. Finally, the teeth in people with OI have often been noted to be smaller than those of people without OI. Because dental development occurs early in life, there is a lack of data surrounding the developmental processes and associated issues in dental development of children with OI. Mice are commonly used models for dental development, yet, this process has not yet been studied in mice. The objective of this study is to compare dental tissue volumes of teeth from mice with OI (oim) and wild type mice (wt) at different developmental stages to determine the degree of volume and gross dental size differences during late growth stages. Three-dimensional models of upper and lower first molars and incisors were created from microCT scans from oim and wt mice. Scans were taken at weaning age (four weeks after birth; "W4") and young adulthood (sixteen weeks after birth; "W16"). Dental tissue volumes were measured using 3D Slicer and normalized to mandibular centroid size. Mann-Whitney U tests were used to compare tissue volumes between genotypes and age groups. At W4 and W16, oim mice had significantly lower dentin volumes and total tooth volumes for upper incisors than wt mice (p < 0.05), with no significant difference between groups for other tooth types at either timepoint. At W16, total tooth volume was significantly lower in oim mice for molars before adjusting for mandible size (p < 0.05). For both oim and wt groups, W16 mice had significantly greater dentin, enamel, and total tissue volumes for lower and upper incisors compared to W4 mice (p < 0.05), as well as greater dentin volumes for lower molars (p < 0.05). These results demonstrate that the trend of smaller teeth in humans with OI also holds for the oim mouse. These differences are present at both the juvenile and young adult life stages. This affirms the oim mouse as a possible model for dental development in humans with OI. Further studies are needed to determine the developmental program of these volume differences at earlier growth stages.Item Effects of Osteogenesis Imperfecta on the Cochlea and Sensorineural Hearing(2022) Huston, Lila Athena; Menegaz, Rachel A.; Handler, Emma; Organ, Jason; Gonzales, LaurenBackground: Osteogenesis 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) any visible variation between WT and OI variants, and 2) assess the encroachment of the otic capsule onto the cochlea by analyzing differences in duct volumes. 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. Methods: 16 week old OIM mice (B6C3Fe a/a-Col1a2oim/J) (n=6) were compared to unaffected wildtype (WT) littermates (n=6) 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. Results: 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 (4-15%; p< 0.05), indicating potential unilateral effects. 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< 0.05). Discussion: 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 Efficacy of Using Zoledronate for Prevention of Craniofacial Fractures in Mice with Osteogenesis Imperfecta(2024-03-21) Pattillo, Bryce; Miller, Courtney A.; Emmanuel, Tanusha; Crowe, Nicole M.; Menegaz, Rachel A.Osteogenesis imperfecta (OI) is a genetic disorder of type I collagen that results in increased bone fragility, increased fracture rates, and abnormalities of the limbs, vertebral column, and craniofacial skeleton. Long-lasting bisphosphonate drugs, like zoledronate, are used in children with OI to increase bone mineral density and prevent skeletal fractures. Zoledronate increases osteoclast apoptosis, thus reducing relative rates of bone resorption and increasing formation rates. Previous experimental research on the efficacy of zoledronate has focused largely on the postcranial skeleton (e.g. limbs). The goal of this study is to investigate if zoledronate reduces the rate of craniofacial fractures in mice with osteogenesis imperfecta. We hypothesize that mice treated with zoledronate will have fewer skeletal fractures of the skull compared to untreated mice. Mice with OI (OIM, B6C3Fe a/a-Col1a2oim/oim) and unaffected littermates (wild-type, WT) were randomly assigned into either control (C) or zoledronate (ZOL) treatment groups (n=5/genotype/group). Mice treated with zoledronate received subcutaneous injections of the drug (80 µg/kg) at 4, 8, and 12 weeks of age. The craniofacial skeleton of all mice was imaged with a micro-CT scanner (20 µm3 voxels) every 4 weeks from 4-16 weeks. 3D models of the craniofacial skeleton were generated in 3D Slicer software, and analyzed for incidence and location of fractures. At 8 weeks, no fractures were observed in WT-C or WT-ZOL mice. However, fractures were observed in both groups of OIM mice. 80% (4/5 per group) of OIM-C and OIM-ZOL mice had skeletal fractures, and the remaining 20% (1/5 per group) had fractured incisors. All skeletal fractures were observed along the zygomatic arch, proximal to the attachment site of the masseter muscle. Both unilateral and bilateral zygomatic fractures were observed. Preliminary data indicates that a single treatment with zoledronate at 4 weeks of age does not reduce the incidence of craniofacial fractures in mice with OI. Additional data is needed to assess if zoledronate improves fracture healing or bone quality outcomes (e.g. BMD) in the craniofacial skeleton, as has been demonstrated in limb bones. Additionally, the prevalence of fractures proximal to skeletal attachment sites for feeding muscles suggestions that muscle-bone interactions are a key component for understanding the origin of facial fractures in this model. Previous work has shown that long-term use of bisphosphonates like zoledronate may have negative outcomes for the craniofacial skeleton, including delayed bone formation, altered dental eruption, and osteonecrosis of the jaw (ONJ). This study suggests that craniofacial health is an important consideration, distinct from postcranial health, when planning interventions for patients with OI.Item Evaluating Ecogeographic Variation in Human Nasal Passages Using In-Silico Decongestion of the Nasal Cycle(2020-05) Thai, Elizabeth; Maddux, Scott D.; Menegaz, Rachel A.; Rosales, ArmandoTo protect the lungs from desiccation and thermal damage, inspired air must be heated to core body temperature (37°C) and 100% saturated with water vapor upon reaching pulmonary tissues. The majority of air conditioning occurs in the nasal passages, where heat and moisture are transferred to inspired air from nasal mucosa via concurrent convection and evaporation. Given that physiological demand for air conditioning is largely dependent on the external environment, many studies have noted strong associations between climate and ecogeographic patterning of human nasal morphology. Specifically, these studies have shown that individuals indigenous to cold-dry environments exhibit relatively longer, taller, and narrower nasal passages than individuals from hot-humid climates. These apparent climate-mediated morphologies are assumed to reflect functional differences, with longer, taller, and narrower nasal passages in cold-dry climates enhancing respiratory heat and moisture exchange via the increased relative mucosal surface area. However, due to the nasal cycle, direct associations between nasal passage dimensions and mucosal surface area to airway volume (SA/V) have been challenging to quantitatively establish. The nasal cycle refers to the alternating congestion and decongestion of the venous sinuses lining the nasal turbinates and part of the septum. In this study, we tested associations between nasal passage height, breadth, and length dimensions and passage SA/V ratio via 3D morphometric assessments of computed tomography (CT) cranial scans in 8 individuals - four of European ancestry (EA) and four of African ancestry (AA). 3D models of the nasal passages were created using 3D Slicer software. Airway models were artificially dilated in-silico to simulate fully decongested nasal passages. Morphometric measurements of passage height, breadth, and length dimensions; mucosal surface area; and airway volume were collected from both congested and decongested airway models. Consistent with expectations, there appears to be no noticeable difference in median congested SA/V ratios (p=0.8) between EA subjects (SA/V=0.99) and AA subjects (SA/V=0.99). There was a trend for EA subjects to have greater median decongested SA/V ratios (SA/V=0.51) than AA subjects (SA/V=0.49), however, this difference did not reach statistical significance with the number of subjects included in our study (p=0.2). Further analysis reveals EA individuals' nasal length to be significantly longer than AA individuals (p=0.028) while all other measurements (nasal height and nasal breadth) demonstrate expected trends but are not significant (all p≥0.8). Our results provide evidence to support that the congestion level of subjects on CT imaging could significantly impact morphometric analysis of the nasal cavity and computational fluid dynamics (CFD) analysis of nasal airflow - and thus is important to consider when creating models for CFD analysis. Future research employing CFD analyses may provide insight into how morphological differences impact intranasal heat and moisture exchange thus providing further insight into how ecogeographic variation in human nasal morphology may reflect climatically adaptive differences in nasal function.Item Harder foods make hardier heads among post-weaning rats(2021) Mitchell, D. Rex; Menegaz, Rachel A.Purpose: The impact that material properties of foods have on the mammalian skull has been studied extensively. However, research that compares cranial morphologies in response to dietary shifts during growth is limited. We analyzed the crania of Sprague-Dawley rats raised on contrasting post-weaning diets. Methods: Four groups of rats were fed different diets from weaning (week 4) to adulthood (week 16): powdered pellets only (SS); hard pellets only (HH); powdered pellets followed by a switch to hard pellets at week 10 (SH); and hard pellets switched to powdered pellets. We employed shape analysis (Geometric Morphometrics) and computational biomechanics (Finite Element Analysis) to quantify the impact of food hardness on the morphology of their crania. Results: We found significant differences in cranial shape between SS and HH groups, and SH and HH groups. In both cases, similar shape differences were found in the region of the temporal zygomatic root, suggesting that a diet of hard foods may have a consistent impact on morphology. Biomechanical modelling demonstrated clear differences in bone stress distributions during incisor biting between diet groups, indicative of bone remodeling in response to the introduction/removal of hard foods; groups fed hard pellets experienced less stress indicating bone deposition for reinforcement. Conclusions: These findings suggest juvenile diets are an important predictor of intraspecific cranial morphology. More extensive analyses incorporating larger sample sizes will help to further elucidate the nature of these relationships and will contribute to our understanding of mammalian osteology and mastication, post-weaning development, and orthodontics.Item Indications of musculoskeletal health in deceased male individuals with lower-limb amputations: comparison to non-amputee and diabetic controls(Springer Nature, 2023-06-01) Finco, M. G.; Finnerty, Caitlyn; Ngo, Wayne; Menegaz, Rachel A.Individuals with lower-limb amputations, many of whom have type 2 diabetes, experience impaired musculoskeletal health. This study: (1) compared residual and intact limbs of diabetic and non-diabetic post-mortem individuals with amputation to identify structures vulnerable to injury, and (2) compared findings to diabetic and healthy control groups to differentiate influences of amputation and diabetes on musculoskeletal health. Postmortem CT scans of three groups, ten individuals each, were included: (1) individuals with transtibial or transfemoral amputations, half with diabetes (2) diabetic controls, and (3) healthy controls. Hip and knee joint spaces, cross-sectional thigh muscle and fat areas, and cross-sectional bone properties (e.g. area, thickness, geometry) were measured. Wilcoxon Signed-Rank and Kruskal-Wallis tests assessed statistical significance. Asymmetry percentages between limbs assessed clinical significance. Residual limbs of individuals with amputation, particularly those with diabetes, had significantly less thigh muscle area and thinner distal femoral cortical bone compared to intact limbs. Compared to control groups, individuals with amputation had significantly narrower joint spaces, less thigh muscle area bilaterally, and thinner proximal femoral cortical bone in the residual limb. Diabetic individuals with amputation had the most clinically significant asymmetry. Findings tended to align with those of living individuals. However, lack of available medical information and small sample sizes reduced the anticipated clinical utility. Larger sample sizes of living individuals are needed to assess generalizability of findings. Quantifying musculoskeletal properties and differentiating influences of amputation and diabetes could eventually help direct rehabilitation techniques.Item Microstructure & Macrostructure Interrelationship in the Growing Hard Palate(2022) Miller, Courtney; Steele, Ashley T.; Organ, Jason; Menegaz, Rachel A.Bone strength is the result of microstructure (bone material properties) and macrostructure (bone size and shape), and deficiencies in either can produce skeletal fragilities with an increased likelihood of injury. The micro- and macro-architecture work together during re/modeling, ensuring that the skeleton is resistant to repetitive loading and preventing fracture. Bone is particularly responsive to loading during the rapid growth occurring in early life. Within the craniofacial complex, the hard palate is a unique structure that undergoes continuous loading due to continuous resting/active tongue pressure and bite forces. Because of this, palatal growth is theorized to drive midfacial growth. The aim of this study is to investigate longitudinal changes in the palate when the relationship between microstructure and macrostructure is perturbed. Here we use the OIM mouse (B6C3FE a/a-Col1a2OIM/J), a strain with a mutation to the structural protein type I collagen, resulting in increased bone fragility and improper biomineralization. We hypothesize that OIM and unaffected wild-type (WT) mice will be most similar in bone micro- and macro-structure in regions of the palate that experience high loading and therefore high rates of bone modeling/remodeling. Mice were micro-CT scanned at two timepoints: week 4 (juvenile) and week 16 (adult). BMD was collected at 3 regions (anterior, mid, and posterior palate). Mann-Whitney U tests were used to compare BMD between genotypes. 28 fixed and 10 sliding landmarks were placed across the palate. Geometric morphologic analyses were conducted to determine variation between genotypes in overall shape and curvature throughout growth. Average BMD decreased along an anteroposterior gradient for all mice. While juvenile OIM mice had lower palate BMD than WT mice at all regions, adult OIM mice had significantly lower BMD at only the anterior and posterior regions but not the midpalate. Procrustes ANOVA revealed significant differences in palatal shape between the genotypes at both the juvenile (p=0.001) and adult (p=0.0015) stages. Principal component analyses revealed that juvenile OIM mice had a shorter anterior palate and broader palate compared to WT mice, while adult OIM mice had a shorter posterior palate than WT mice. OI mice had flatter palatal arches in the coronal plane as juveniles, and in the midsagittal plane as juveniles and adults. Results show significant differences in palatal BMD and morphology between genotypes throughout growth, with fewer significant differences at the adult stage. Increased loading of the anterior palate during incisive gnawing may result in the convergence of bone macrostructure among adult mice, while increased strain at the midpalatal suture may necessitate increased BMD even in the presence of a biomineralization defect. Further research is needed to understand the functional significance of the anteroposterior palatal gradient and its relation to soft tissue attachments, particularly given the difference in oral behaviors between juveniles and adults.
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