Degeneration of the intervertebral disc (IVD) is strongly associated with low back pain which is the leading cause of disability worldwide. Chronic inflammation is a key factor implicated in the pathogenesis of IVD degeneration and one which influences both matrix breakdown and pain associated with IVD pathology. Addressing the inflammatory component of IVD degeneration is as an important clinical target with the potential to both slow disease progression and alleviate pain. However, improved understanding of how inflammation develops and contributes to the progression of disease is required in order to inform future clinical interventions. This dissertation aims to improve understanding of how inflammation contributes to disease pathology through investigating how pro-inflammatory cytokines arise and are transported within the IVD, and how pro-inflammatory cytokines contribute to the altered disc mechanics and mechanobiology observed in disease. This dissertation consists of four aims using both cell and organ culture models to investigate these topics. The first aim uses a three dimensional cell culture model to (i) characterize the inflammatory kinetics of degenerated human nucleus pulposus cells and (ii) evaluates how the timing and choice of antiinflammatories influence the progression of the inflammatory cascade. The second aim develops a dynamic loading system for organ culture of human and bovine IVDs, which is then used in the third aim to create an inflammatory organ culture model investigating (i) whether pro-inflammatory cytokines can penetrate the “immune-privileged” IVD and what the dominant mode of transport is within the IVD (diffusion v convection) and (ii) the mechanism through which pro-inflammatory cytokines influence whole IVD mechanics. The final aim investigates how inflammatory mediators influences mechanotransduction within the IVD through examining the relationship between TNFα and the osmo-sensitive TRPV4 ion channel and characterizing how altered TRPV4 expression, observed in simulated disease, impacts IVD cell metabolism. Together, results suggest a mechanism through which pro-inflammatory cytokines, possibly resulting from injury of surrounding spinal tissues, can penetrate intact IVDs and very quickly induce matrix degradation which directly alters both the mechanics and mechanotransduction within the IVD. Overall, this work demonstrates a novel mechanism of how inflammation may be involved in the initiation and progression of IVD degeneration.