Degeneration of joint tissues is associated with a multitude of diseases, such as osteoarthritis, rheumatoid arthritis, and osteoporosis. The synovial membrane secretes synovial fluid, consisting of hyaluronan and other components that help to lubricate the joint capsule. During disease, both the membrane and fluid exhibit an inflammatory phenotype and reduced function. Cortical bone structure has been shown to deteriorate in both quality and strength with the onset of joint disease. While there are a number of studies that have characterized the biological changes that are associated with disease progression, few have incorporated the role of the mechanical environment. Thus, this thesis aims to probe the relationships between synovial and bone health, inflammation, hyaluronan, and mechanical loading.

First, we assessed the sensitivity of synovial fibroblasts to mechanical stimulation. Although synthesis and breakdown of hyaluronan by synoviocytes drive hyaluronan content in synovial fluid, little is known about how the extent to which mechanical stimulus alters hyaluronan turnover. We show that synoviocytes are not only sensitive to cyclic strain, but also strain magnitude, impacting hyaluronan synthase and hyaluronidase expression and cytokine production. Next, we determined the dependency of bone health on hyaluronan synthesis. While hyaluronan is known to play a role in bone mineralization and turnover, the impact of altered hyaluronan production on bone morphology and strength is poorly understood. We demonstrated that loss of hyaluronan synthase 1 or 3 distinctly impacts cortical bone morphology, matrix composition, and mechanical properties. We also assessed the impact of hindlimb disuse and systemic inflammation in a mouse model, showing that radiation and unloading have a compounded effect on cortical bone properties and synovial membrane transcriptomics. Finally, we assessed the ability for exercise to mitigate joint tissue deterioration due to hindlimb unloading. We found that exercise significantly impacts bone matrix composition, rescues bone strength, and promotes extracellular matrix remodeling in synovial tissue.

Overall, this research highlighted the sensitivity of the synovial membrane and bone tissues to their surrounding mechanical environment and their interdependency with hyaluronan content and inflammation. Identifying the mechanosensitivity of synovial and bone tissue, especially in the context of hyaluronan and inflammation, may lead to the development of new therapeutics towards preventing joint tissue degradation.