Cardiac Function and Aging in Mild and Severe Mouse Models of Osteogenesis Imperfecta
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| Published in: | ProQuest Dissertations and Theses (2025) |
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| Abstract: | Osteogenesis imperfecta (OI) is a heritable connective tissue disorder, commonly called brittle bone disease, occurring in approximately 1 in 15,000 births. OI is genetically and clinically heterogeneous with over 1500 known mutations ranging in clinical severity from mild with few fractures and skeletal deformity to severe fragility and perinatal lethality. Mutations in the type I collagen genes, COL1A1 and COL1A2, are present in roughly 85% of patients with OI, with other OI-causative mutations arising from gene loci that affect collagen trafficking, processing and post-translational modifications. The term, osteogenesis imperfecta, arises from the imperfect bone formation which results in bone fragility, low bone mineral density and long bone bowing. While bone fragility is the most characterized phenotype in OI, there are many extra-skeletal phenotypes such as skeletal muscle weakness, cardiopulmonary complications, and skin fragility. There is no cure, and current treatment options focus on improving the skeletal complications. OI patients life spans are reported to be reduced by 7-10 years primarily due to cardiopulmonary complications. While pulmonary phenotypes have been investigated in the OI patient community and in multiple mouse models, the cardiac complications have been less studied. As cardiac dysfunction in commonly linked with aging, it is also important to understand the impact of age on heart health in OI.My research sought to better understand the presence of cardiac complications and cardiac consequences of aging in OI by preclinical investigations in the osteogenesis imperfecta murine (oim/oim) model of severe human type III OI. We hypothesized that oim/oim mice would have compromised cardiac function that would worsen with increasing age potentially contributing to shortened life span. To test this hypothesis, we evaluated overall survival to 18 months of age and cardiac function in oim/oim and wildtype mice through in-vivo 7T MRI and echocardiography. We determined that male oim/oim mice have decreased lifespan, with only 50% of mice surviving to 18 months, an approximate human age of 56-59 years, and that female oim/oim mice did not exhibit early mortality compared to their wildtype littermates. Additionally, male oim/oim mice exhibited decreased cardiac function and valvular dysfunction at 18 months of age compared to age and sex-matched wildtype littermates. Furthermore, to assess arrhythmogenesis as well as cardiomyocyte health in the oim/oim mouse, isolated hearts and cardiomyocytes were tested for function during stress conditions of preload challenge and increased frequency of contraction, respectively. Our findings demonstrate that oim/oim mice have an increased risk of arrhythmias as a potential contribution of cardiac dysfunction, while isolated oim/oim cardiomyocyte function was equivalent to wildtype cardiomyocyte function. These findings suggest that the type I collagen mutations and the extracellular matrix are likely the driver of cardiac dysfunction in OI and not aberrant cardiomyocyte cellular function. Finally, we also sought to investigate cardiac function in a mild to moderate type I/IV OI mouse model, the +/G610C mouse, with a mild skeletal phenotype. We hypothesized that +/G610C mice would present with cardiac dysfunction at 18 months, but to a lesser degree than the severe oim/oim mouse. To this end, only male +/G610C mice were evaluated, as female mice were not affected in the severe oim/oim model. Survival at 18 months was equivalent in male wildtype and +/G610C mice, and cardiac function appeared to be equivalent at 4 and 18 months of age in male +/G610C mice and age-matched wildtype littermates. These findings suggest that less severe type I collagen variants may have reduced risks for development of cardiac dysfunction. However, a limitation of this study is that wildtype laboratory mice have an average lifespan of 28 months, and 18 months of age may have been insufficient to characterize cardiac function and aging in the +/G610C mouse. Overall, my research was the first to show altered lifespan in the preclinical oim/oim mouse model, with the cardiac manifestations as a potential contributor to early mortality. I am also the first to show age, sex and severity dependent phenotypes in the heart, indicating that further studies are needed to fully elucidate the role of type I collagen defects in heart health in OI. My work revealed that at the cellular level cardiomyocyte health does not appear compromised, suggesting that type I collagen mutations primarily compromise the extracellular matrix and not cardiomyocyte function during stress. Oim/oim mouse hearts exhibited an increased risk for developing arrythmias as compared to wildtype hearts. This body of work contributes to a growing awareness of the extra skeletal manifestations of OI as a type I collagenopathy in aging. Future natural history studies that evaluate aging in a temporal manner, as well as mechanistic studies of cardiac health in OI remain to be pursued, these novel findings emphasize the need for further cardiovascular research and careful cardiac monitoring for the OI patient population and contributes to the overall knowledge of type I collagen’s role in cardiac health. |
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| ISBN: | 9798265469427 |
| Source: | ProQuest Dissertations & Theses Global |