Date of Award
12-20-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Low back pain (LBP) is the number one musculoskeletal cause of disability with a lifetime prevalence of up to 85%. The causes of LBP are multifactorial with potential contributions from factors such as tissue injury and degeneration as well as social economic and psychological factors. Intervertebral disc (IVD) degeneration is associated with 26-40% of LBP cases and in a 2015 meta-analysis, it was estimated that a total 403 million people suffer from symptomatic IVD degeneration. IVD degeneration is characterized by loss of hydration in the nucleus pulposus (NP), damage accumulation in the annulus fibrosus (AF) and calcification of the cartilaginous endplates (CEPs). Aging, genetics, disease, mechanical overload and injury all can contribute to the degeneration of the IVD. The IVD response includes inflammation, catabolism, and neoinnervation and vascularization. Animal models provide a useful tool for studying mechanisms of IVD degeneration that may lead to LBP. Mouse IVDs share many key similarities with the human IVD in morphology and in the process of degeneration. Needle puncture of both caudal and lumbar IVD is a well-established model to induce IVD degeneration. Lumbar puncture provides a model more analogous to discogenic LBP. However, lumbar puncture is an invasive surgical procedure that can make it difficult to discern the contributions of IVD injury from the damage to the surrounding tissues. Caudal puncture offers an easily accessible alternative to lumbar puncture. IVD degeneration following caudal puncture has been extensively demonstrated; however, little insight into the progression of innervation and vascularization of the caudal IVD has been established. This dissertation aims to establish caudal puncture as a non-invasive alternative to lumbar puncture and utilize this model to assess bone-IVD crosstalk. To answer these questions, the following dissertation is divided into two specific aims. The first aim quantifies the progression of IVD injury response following caudal puncture by looking at IVD degeneration, cytokine production, and innervation and vascularization of the IVD. The second aim investigates bone-IVD crosstalk following caudal IVD injury. The boney endplate sits at the interface of the IVD and vertebral body and is hypothesized to respond to the change in mechanical environment following puncture and cytokine production from the cells in the degenerating IVD. The receptor for advanced glycation end-products (RAGE) was hypothesized to be a key mediator of bone-IVD cross talk. This aim uses both a global RAGE-null and RAGE fl/fl LysM-Cre mouse models to investigate the role of RAGE signaling ubiquitously and specifically in myeloid cells in bone-IVD crosstalk following caudal puncture. Overall, these findings will demonstrate the utility of caudal puncture as a IVD degeneration model, will spotlight bone-IVD crosstalk in IVD injury response, and establish the importance of RAGE in the response of the vertebral endplate to IVD injury.
Language
English (en)
Chair
Simon Tang
Committee Members
Erica Scheller; Lori Setton; Matthew Silva; Yousef Abu-Amer