PROQUEST: 2447566191
Osteoarthritis (OA) of the knee is a prevalent and painful disease, affecting almost 4% of the global population. While this disease is a major cause of disability in the elderly and a severe socio-economic burden, there is still no cure or robust treatment to slow disease progression. Clinical treatments aim to manage pain and maintain joint function, culminating in joint replacement once the joint structures have become significantly degenerated. Unsurprisingly, knee OA is considered one of the main healthcare challenges for the decades to come.
Improving solutions for patients with knee OA requires a better understanding of the disease mechanisms. While joint injuries are a significant risk factor in OA development (post-traumatic OA, PTOA), in many cases, the initial disease causation is unknown (idiopathic OA, IOA). Literature suggests that structural, mechanical, and biological factors on many scales are involved and interact in both PTOA and IOA development. Only by testing multiple factors and their interactions is it possible to understand disease pathogenesis and ultimately develop effective prevention, intervention, and treatment strategies.
Therefore, the overall goal of this thesis project was to test for differences in and interactions between structural, mechanical, and biological factors in populations at risk of developing PTOA and IOA. Specific aims include the following:
The first study in this dissertation tested a cohort of subjects at risk of developing PTOA due to partial medial meniscectomy. In this population, limb differences in both transverse and sagittal plane gait mechanics differed between walking and stair traversing activities. These findings provide valuable insight into the role of the meniscal structure in the joint during dynamic activities. Specifically, the results emphasize the meniscal function in guiding knee kinematics. These alterations in knee kinematics can change the location of cartilage contact stress, potentially disrupting the mechanical and metabolic homeostasis of cartilage and initiating tissue degeneration (OA). This study may provide novel information for post-operative care as the results indicate the need to sufficiently challenge the knee joint both in dynamic load and range of motion to elicit differences in clinically meaningful kinematic measures after meniscectomy.
To test the whether these measured kinematic limb differences persist longer-term after medial meniscectomy, a sub-cohort of the post-meniscectomy population was tested both at seven and 33 months post-operation. The results from these analyses indicate that the sagittal kinematics, specifically dynamic flexion angle ranges of motion (ROM), can change up to two years after operation. Interestingly, the meniscectomized knee ROM values became more like that of a control population with time past surgery. Furthermore, these kinematic changes were correlated with between-time point changes in flexion and extension moments, which are resisted by the quadriceps and hamstring. Therefore, the observed kinematic changes may be attributable to increased thigh strength and/or activation at the time of follow-up compared to baseline. Overall, the meniscus structure seems to provide important stabilization of the knee during dynamic activities, and the correlation between knee kinematic and the flexion moment suggest that injuries to the tissue can lead to neuromuscular adaptations in order to potentially increase the patient’s sense of stability. While larger studies are necessary, the first two studies presented in this thesis provide important insights into structural and mechanical factors involved in PTOA development after meniscectomy.
Idiopathic OA development is a difficult pathology to study, as early structural changes to the joint tissues can be symptomatically silent for years. The final two studies presented in this thesis utilized a unique cohort of subjects who are in the very early stages of IOA development. Specifically, these individuals are asymptomatic with no prior knee or lower limb injury, but they have magnetic resonance imaging (MRI) evidence of cartilage loss (“Pre-OA”). The first of two studies tested for sagittal plane knee mechanics and systemic inflammation differences between the Pre-OA group and an asymptomatic control cohort without any MRI pathologies. The Pre-OA subjects displayed kinematic and kinetic differences from the control group that are similar to differences seen between symptomatic OA patients and control subjects and between severe and mild OA patients. Namely, the Pre-OA subjects were less extended near terminal stance and had decreased maximum extension moment in terminal stance than control subjects. Furthermore, the Pre-OA group had greater systemic inflammation (tumor necrosis factor-alpha, TNFα) compared to the control subjects. The fact that the observed gait alterations and elevated inflammatory markers in this population were consistent with differences seen in patients with medial compartment OA suggests a general response to the early stages of joint degeneration that is consistent with a continuum of structural, mechanical, and biological changes throughout the OA disease process beginning long before clinical diagnosis. This is a key finding for a better understanding of OA development, and with the addition of future longitudinal studies to test when or whether these subjects go on to develop OA, these results may provide measureable predictors and means of disease detection and interventions for IOA.
The aim of the final study presented in this thesis was to test the interaction between gait mechanics, serum inflammation level, and cartilage structure (average cartilage thickness) in the aforementioned Pre-OA cohort. It was found that both systemic inflammation and coronal plane gait kinetics were positively correlated with femur and tibia regional average cartilage thickness values. This positive relationship between TNFα and cartilage thickness may be an indication of early cartilage swelling due to the structural cartilage defects in the joint. In general, the results support a multi-factor, multi-scale model of OA pathogenesis; with mechanical and biological factors so closely related to structural morphology, slight alterations in either gait mechanics or inflammation can greatly upset cartilage homeostasis, potentially progressing the observed cartilage defects and developing clinical OA symptoms. Furthermore, these results provide insight into potentially modifiable factors involved in early and pre-OA disease interventions.
Together, this thesis presents four studies probing the pathogenesis of OA by testing for structural, mechanical, and biological differences in subjects at increased risk of developing PTOA and IOA.