Characterization of Bone Pathology in Sickle Cell Disease and Therapeutic Strategies

Sickle cell disease (SCD) is a genetic hemoglobinopathy that has grown into a global health concern. While the advances in medical treatment and management of SCD during childhood have drastically improved the overall survival of children, the transition from pediatric to adult services is significantly inadequate in comparison. Life expectancies of patients with SCD in first world countries such as the United States are shortened to averages of 42 and 48 years for men and women, respectively. Despite the increasing number of people living with SCD, remarkably, few detailed studies have described the clinical course and complications of the disease over time. Interrupted tissue perfusion and vaso-occlusion by rigid sickle red blood cells (RBC) are considered the primary pathological mechanisms, however little is known about how SCD influences the physiology of surviving cells and tissue. Hemolysis, which is traditionally viewed as a secondary contributor to the sickle pathology, not only initiates and propagates occlusive crises, but the resulting chronic systemic oxidative stress may play a role in altering organ function. Asymptomatic vascular damage begins years before clinical symptoms manifest, at which point the damage is irreversible and progresses throughout life until multi-organ occurs. Bone is highly susceptible to oxidative stress and damage; however, the impact of SCD on bone health is significantly under-investigated despite its importance in maintaining overall health. The objective of this thesis was to characterize the pathophysiology of SCD on bone tissue growth and development. Our approach utilizing the Townes transgenic sickle mouse model allows for native bone degeneration to be thoroughly examined longitudinally at the macro- and microscopic level, which is clinically unfeasible. The theoretical and clinical significance accrued across this thesis will address the gaps in knowledge regarding the role of sickle RBC hemolysis in tissue degeneration, the onset and progression of sickle osteonecrosis, gender differences in sickle pathology, the influence of chronic oxidative stress on bone cell physiology, as well as the benefits of antioxidant therapies on sickle bone quality. This thesis will serve as the foundation for the future development and improvement of clinical diagnostic tools and non-erythroid tissue-based therapies for SCD