Osteoarthritis (OA), a degenerative joint condition characterized by progressive loss of articular cartilage and other joint tissue changes, is the most common cause of disability in the United States. OA is a disease with multifactorial etiology resulting in heterogeneous disease onset and progression, but the same ending of joint degeneration. Current treatment options are focused on managing OA symptoms, specifically pain, but do not treat the underlying cause of disease. A major hurdle for better therapies is the lack of understanding of OA disease initiation and progression, especially at early stages of prior to clinical symptoms. This thesis present two independent projects seeking to understand the roles of biochemical and biomechanical factors in OA development.

In the field of OA research, biochemical changes are understood to occur in early OA. There is an increase in cartilage metabolism and a decrease in catabolism, which contributes to cartilage loss and other joint tissue changes. Inflammation is thought to be a major driver of these biochemical changes underlying structural changes. One aspect of this thesis focuses on understanding inflammatory dynamics driven by master transcriptional regulator NFkappaB and how it may be related to cartilage structural changes. Results from this study showed that NFkappaB driven inflammation, visualized via bioluminescence imaging, peaks early in a post-traumatic OA (PTOA) mouse model and that structural modifications, visualized as collagen fiber thickness and orientation changes through second harmonic generation imaging, also occur in early OA across different cartilage layers.

The second project of this thesis is focused on understanding the interplay between biochemical (specifically glucose) and biomechanical factors in OA progression utilizing a novel ex vivo joint culturing system, the Joint-in-Motion 1 (JM1) device. In this study, whole mouse knee joints were cultured in media solutions with variable glucose and osmolarity with dynamic input. While joint spatial orientation, cell numbers, and extracellular matrix collagen II was preserved, proteoglycan was lost only in joints cultured in high glucose with dynamic movement. This study revealed the synergistic effects of biomechanical and biomechanical factors in OA development and highlights a possible role for glucose in priming the joint for damage via biomechanical stress.