Osteoarthritis (OA) is a debilitating and painful disease of synovial joints that affects an estimated 27 million people in the United States. Limitations to current treatments include the ineffectiveness of conservative treatments, as well as the risks, costs, and limited lifespan of surgical interventions. The progressive joint degeneration of OA involves the modulation of cartilage extracellular matrix metabolism towards degeneration. Mechanical loading is known to play a central role in cartilage function, both in the normal and pathological settings. This dissertation provides important insights into how mechanical factors the influence the function of articular chondrocytes in ways that are relevant to cartilage maintenance and disease.

The transient receptor potential vanilloid 4 (TRPV4) ion channel is implicated in chondrocyte mechanical signal transduction via changes in tissue osmolarity. This dissertation characterizes the role of TRPV4 in cartilage maintenance during both normal and abnormal loading. The physiologic effects of dynamic compressive loading on chondrocyte function are examined with regard to TRPV4-mediated mechanical signal transduction. The role of TRPV4 in obesity model of osteoarthritis and stem cell differentiation potential is also examined. Lastly, an investigation into the role of TRPV4, specifically in articular cartilage, in destabilization-induced osteoarthritis is detailed. The results presented in this dissertation that describe the mechanical regulation of chondrocyte metabolism via TRPV4-mediated Ca²⁺ signaling are predicted to contribute to the development of novel pharmaceutical and biophysical interventions for the treatment of osteoarthritis.