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Elucidating the role of iron in the pathogenesis of idiopathic osteoarthritis in the Dunkin-Hartley animal model




Burton, Lindsey Hammond, author
Tjalkens, Ronald, advisor
Santangelo, Kelly, advisor
Legare, Marie, committee member
Goodrich, Laurie, committee member
Argueso, Lucas, committee member

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Osteoarthritis (OA) is the most prevalent musculoskeletal disorder, affecting millions of individuals worldwide. While OA is characterized by the progressive loss of articular cartilage, it is now widely accepted to be a whole joint disorder, with changes such as synovial hyperplasia, subchondral bone remodeling, and osteophyte formation accompanying cartilage degeneration. The knee is one of the joints most affected by OA. Patients with knee OA exhibit painful and/or limited mobility as a consequence of the disorder, resulting in an increased risk of comorbidities such as heart disease, obesity, diabetes, and depression. Unfortunately, the mechanisms driving OA pathogenesis remain poorly understood, and there are no effective therapies available for treating the disorder. Therefore, there is a need to understand factors contributing to OA to identify potential targets for combating the condition. Iron is the most abundant mineral in the human body and is essential for conducting numerous physiologic processes. However, unbound or partially-liganded iron can participate in redox reactions that produce reactive oxygen species and free radicals capable of inciting tissue damage. As such, iron needs to be tightly managed within the body. Mammals do not possess a regulated mechanism for excreting iron, and iron progressively accumulates within tissues throughout the aging process. Primary/idiopathic OA does not have any known, identifiable cause for disease development, but the largest risk factor associated with the disorder is advancing age. To address this gap in knowledge, we designed a series of experiments to elucidate the contributions of iron to the pathogenesis of idiopathic OA. The main animal model used for this work is the Dunkin-Hartley guinea pig, which spontaneously develops age-related OA with a histopathology similar to that observed in humans. In the first study, we quantified tissue iron levels at different ages in OA-prone Dunkin-Hartley guinea pigs relative to an outbred, control strain not used in OA research. While the control strain accumulated iron in the liver with age, but not within cartilage, the Hartleys demonstrated a significant increase in cartilage iron concentration at 7-8 months-of-age. This increase in cartilage iron concentration was more significant in males, though it was also observed in females. As this timepoint corresponds to a moderate stage of disease progression, this finding suggests that iron may play a role in OA development and/or progression in Hartley guinea pigs. This concept was supported by gene expression analysis of iron-related genes. Notably, both male and female Dunkin-Hartley guinea pigs had decreased transcript expression of ferritin heavy chain and ferroportin at 7-8 months, which may contribute to cartilage iron accumulation at this age by inappropriately storing iron in chondrocytes. Because of this intriguing association, we wanted to investigate the gene expression changes occurring with systemic iron manipulation in knee joint tissues. Exogenous iron overload resulted in worsening of OA pathology in the disease-resistant Strain 13 guinea pig. The systemic administration of iron dextran caused iron to accumulate within articular cartilage from a diarthrodial joint environment and was accompanied by gene expression changes within knee tissues. Notably, systemic iron overload altered the expression of several iron-related genes in this control strain, indicating that both the cartilage and a large adipose depot, the infrapatellar fat pad, were able to detect and respond to changes in tissue iron levels in the presence of joint pathology. Conversely, systemic iron deficiency, achieved by supplying an iron deficient diet, decreased cartilage lesions within OA-prone male Hartley guinea pigs. In this proof-of-principle study, the reduction in cartilage iron concentration was accompanied by the altered expression of two iron transport genes, the importer transferrin receptor 1 and the cellular iron exporter ferroportin. As iron deficiency is not a recommended pursuit, we investigated the effects of systemic iron reduction, without clinical iron deficiency or anemia, on OA pathogenesis. The commercially available pharmacologic iron chelator deferoxamine (DFO) was used to reduce total iron levels in the body of male and female Dunkin-Hartley guinea pigs. In males, administration of DFO was successful at reducing tissue iron levels both systemically and in a diarthrodial joint environment, and this was accompanied by a significant decrease in the severity of cartilage lesions. The reduction in joint pathology observed with treatment was largely attributed to a decrease in chondrocyte cell death; this finding was supported by the decreased expression of several proapoptotic genes within knee articular cartilage. Conversely, tissue iron levels were not altered by administration of the same dose of DFO in females, suggesting the presence of sex differences in systemic iron homeostasis. There was a relative reduction in histologic OA score in treated female animals, which may be due to the beneficial mobilization of iron by DFO that was also noted in males. The modest reduction in female joint pathology with treatment was largely driven by decreased tidemark advancement. Tidemark replication is associated with articular cartilage mineralization and was almost completely absent in all males evaluated, implying there may also be differences in OA pathogenesis between male and female Dunkin-Hartley guinea pigs.


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articular cartilage
guinea pig


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