The roles of iron, the infrapatellar fat pad, and dietary factors in the Hartley guinea pig model of spontaneous osteoarthritis
Date
2018
Authors
Radakovich, Lauren, author
Santangelo, Kelly, advisor
Olver, Christine, committee member
MacNeill, Amy, committee member
Foster, Michelle, committee member
Pagliassotti, Michael, committee member
Journal Title
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Volume Title
Abstract
Osteoarthritis (OA) is the most prevalent musculoskeletal disorder across the world, affecting close to 300 million people. The disease manifests as degeneration and loss of articular cartilage, synovial hyperplasia, formation of osteophytes, subchondral bone remodeling, and joint space narrowing. These changes result in decreased range of motion as well as painful mobility in affected individuals. The knee joint is the most commonly afflicted joint. Osteoarthritic changes may develop secondary to a localized injury, referred to as post-traumatic OA. Degenerative changes can also develop without an inciting cause, which is referred to as spontaneous, or primary OA. Spontaneous OA is an insidious disease that is associated with aging, and, more recently, with obesity. The mechanisms contributing to disease development are not yet fully characterized, which has impeded implementation of successful treatment options. Currently, there are no treatments that are able to restore degraded cartilage. Thus, most patients with symptomatic knee OA undergo costly total knee joint replacement surgeries. The aims of this dissertation were to explore the roles that aging-associated iron accumulation, the infrapatellar fat pad, and calorie restriction with various diets may play in OA development. These studies were performed in the Hartley guinea pig, one of the only small animal models of spontaneous OA. One study was performed in Strain 13 guinea pigs, a strain that is OA-resistant. Iron is an element that acts as a double-edged sword. It is essential for oxidative phosphorylation and heme synthesis, yet its redox potential means it has the capacity to incite oxidant damage when present in excess. As there is no direct excretion mechanism for iron, it tends to accumulate slowly within tissues over time. This cellular iron accrual has been implicated in many degenerative diseases associated with aging, but its potential role in spontaneous OA has not been well-studied. In our first studies, we demonstrated that systemic iron levels have an influence on OA. We were able to induce bony and cartilage lesions in OA-resistant Strain 13 guinea pigs by systemic administration of iron dextran. Immunohistochemistry (IHC) indicated higher levels of lipid peroxidation in cartilage, menisci, the infrapatellar fat pad (IFP), and synovium in the iron overload animals. Special stains revealed that iron content was significantly higher in the IFP in these animals, which we propose serves as a local depot of oxidant damage to the knee joint. In a parallel study, we fed OA-prone Hartley guinea pigs an iron deficient diet to determine if reducing systemic iron levels may have a protective effect on the knee joint. Cartilage lesions were significantly lower in the iron deficient diet group compared to controls. Likewise, IHC for lipid peroxidation revealed less oxidant damage in the iron deficient pigs. However, no differences were noted in knee joint iron content, so the exact mechanisms for the lessened OA remain unclear. Because the iron overload study pointed to the IFP as a potential iron depot, we wanted to further characterize how this adipose tissue contributes to overall knee joint homeostasis. First, we demonstrated that quantitative iron content in the IFP was increased in aged, osteoarthritic guinea pigs compared to young, healthy animals. Gene expression data collected suggested that dysregulated iron trafficking, particularly increased expression of ZIP14 – which has been linked to pathologic iron uptake in other conditions – may be contributing to this aging-associated increase of iron in the IFP. Because of our suspicion that the IFP may be inciting local oxidant damage to the knee, we surgically removed it from a set of young Hartley guinea pigs. An identical sham procedure was performed in the contralateral limb. Four months post-surgery, animals were collected to evaluate OA in both limbs. Both cartilage and bony OA scores were markedly decreased in the IFP removal limb compared to the sham surgery limb. It is possible that removal of the IFP removed a source of local inflammatory mediators and iron, which resulted in lessened OA. As the IFP was replaced by a thick band of fibrous connective tissue, increased joint stability was also considered a contributing factor. Future studies will more closely examined contributions of biomechanical factors that may be at play. Finally, we aimed to determine how dietary manipulations may influence early OA, as previous studies suggest that calorie restriction may improve end-stage OA. Additionally, many studies have shown high fat diet (HFD)-induced obesity plays a role in OA development due to the inflammatory nature of excess adipose tissue. In our study, we demonstrated that calorie restriction with a low fat regular chow diet, but not a calorie restricted HFD, delayed onset of OA in Hartley guinea pigs. In fact, the HFD group had higher levels of systemic inflammation than the restricted regular chow group. The HFD group had similar levels of inflammation and OA scores as obese animals. Thus, we concluded that the pro-inflammatory nature of a HFD supersedes any positive effects of calorie restriction in the onset of spontaneous OA.
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Subject
iron metabolism
oxidant damage
osteoarthritis
guinea pig