ABSTRACT. Meniscal injuries are a significant clinical problem as each year 850,000 meniscal surgeries are performed in the United States and nearly twice as many worldwide. Meniscal tears in the avascular inner zone of the tissue do not heal well with suturing or conservative treatments and can ultimately lead to the development of osteoarthritis (OA). Therefore, new strategies are needed to enhance endogenous meniscus repair and tissue regeneration. The menisci play a critical biomechanical role in the knee, providing load support, joint stability, and congruity. Meniscus tissue is maintained through a balance of anabolic and catabolic activities of meniscus cells. These cellular activities are controlled not only by biochemical factors in the joint but also by physical factors associated with joint loading. Mechanobiology, which is the influence of mechanical factors on the biologic response of cells, is important in converting physical signals into metabolic and inflammatory responses in meniscus. However, the mechanisms by which mechanical signals are transduced in meniscus cells have yet to be identified. Our overall goal is to identify critical meniscus mechanotransduction pathways and modulate these pathways to promote meniscus repair and prevent OA development. Our work has shown that transient receptor potential vanilloid 4 (TRPV4) is a critical component in cartilage mechanotransduction and metabolism. The activation of TRPV4 can block IL-1 induced catabolic responses and also increases cell migration and proliferation, which are important processes to enhance tissue repair. While we have found that TRPV4 is expressed in the meniscus, the function of this mediator in meniscus health and disease is currently unknown. In this proposal, we will determine how mechanotransduction occurs through TRPV4 in meniscus and identify modulators of this pathway that will be used to enhance tissue repair and prevent OA development. We hypothesize that mechanotransduction by TRPV4 plays a key role in meniscus metabolism and can be modulated to enhance meniscus repair and prevent the development of OA. In this proposal, we will determine the effects of mechanical stimulation on TRPV4-mediated metabolism in healthy meniscus cells. Next, we will elucidate alterations in TRPV4-mediated mechanotransduction pathways in meniscus pathology. Finally, we will enhance integrative meniscus repair and prevent the development of OA by modulation of mechanotransduction pathways. In this proposal, we will identify the key signaling pathways downstream of TRPV4 that may function as novel drug targets to 1) treat patients with immobilized joints to simulate exercise and maintain joint health; 2) enhance meniscus tissue regeneration using tissue engineering strategies; and 3) enhance meniscus repair and prevent the development of OA. Novel therapeutic targets identified in this proposal can subsequently be developed into drugs to enhance meniscus repair and prevent the d...