Date of Award
Doctor of Philosophy (PhD)
Low back pain (LBP) is one of the most common and debilitating musculoskeletal disorders in the world, with a lifetime prevalence above 80%. The cause of LBP is multifactorial, with intervertebral disc (IVD) degeneration being one of the most prominent contributors to its development. IVD degeneration occurs due to aging, aberrant mechanical loading, and injury. The IVD responds to these stimuli and experiences inflammation, catabolism, neovascularization, and innervation. While the degenerative cascade is well characterized, how the IVD transduces mechanical loading and injury stimuli into a degenerative response is still poorly understood. Mechanosensitive ion channels are one mechanism that musculoskeletal tissues use to transduce the complex loads they experience. One potential ion channel that acts a mechanical mediator in the IVD is TRPV4. TRPV4 is an osmotically sensitive ion channel that is Ca2+ preferential and has been found to have a significant transducing role in cartilage and chondrocytes. As the IVD undergoes osmotic changes during mechanical loading, there is potential that TRPV4 mediates the IVD’s biologic response to mechanical stimuli. Limited studies have found that TRPV4 mediates mechanical-induced inflammation in the IVD cells, though no study has evaluated its role in mechanically-induced degeneration at the tissue scale. Further, no studies have evaluated TRPV4 in injury-induced degeneration. This dissertation aims to elucidate TRPV4’s role in IVD response to mechanical loading and to understand how TRPV4 mediates the inflammatory response at the tissue-level scale. Additionally, how TRPV4 regulates IVD tissue response to injury through inflammatory factors was explored. To answer these questions, the dissertation was divided into three specific aims. The first aim validates the need to study TRPV4 at the tissue-level scale due to its effects on the extracellular matrix (ECM) and studies the downstream pathway of TRPV4 activation in the IVD. The second aim uses a whole tissue culture model to study the role of TRPV4 in both static and dynamic loading scenarios and to determine if TRPV4 inhibition is protective against degeneration. The downstream pathway of TRPV4 was further explored to better understand how it regulates response to loading. The final aim of the dissertation investigates if TRPV4 also has a role in IVD response to injury through its influence on inflammation. This aim utilizes both an in vitro and in vivo transgenic model to answer this question. The culmination of these findings will demonstrate how TRPV4 is a vital mediator for mechanically-induced inflammation and degeneration, and through its regulation of inflammation, also contributes to IVD injury response.
Farshid Guilak, Jessica Wagenseil, Spencer Lake, Erica Scheller,
Available for download on Wednesday, May 15, 2024