Degree
Doctor of Philosophy
Program
Physiology
Supervisor
Dr. Cheryle Séguin
2nd Supervisor
Dr. Frank Beier
Joint Supervisor
Abstract
Intervertebral disc (IVD) degeneration is a complex and multi-factorial process that is influenced by aging, genetic predispositions and environmental influences, such as altered mechanical loading. While recent studies have begun to characterize changes in the IVD associated with degeneration, the underlying etiology remains elusive. It is thought that the loss of notochord cells from the nucleus pulposus (NP) is one initiating factor contributing to the cascade of disc degeneration. However, questions remain about the function of notochord cells within the disc, including their capacity as tissue specific progenitor cells for the nucleus pulposus. We have demonstrated, with the use of the novel notochord-specific Cre mouse (Noto-Cre), that all cells in the adult NP are derived from the embryonic notochord (Chapter 2). Using this mouse strain, we performed transcriptional profiling paired with bioinformatic analysis of NP tissues from various time points and determined that TGF-β, PPAR and PI3K-AKT pathways are associated with NP aging, while mineralization, calcium and WNT signalling pathways are associated with NP degeneration (Chapter 3). We further characterized the proteomic signature of the healthy murine IVD to gain insight into the composition of this complex structure and provide a comprehensive catalogue of proteins enriched within the disc (Chapter 4). Lastly, we studied the effects of mechanical loading, in the form of whole- body vibration on the intervertebral disc. Whole-body vibration platforms are becoming increasingly popular in the fitness industry as well as in clinical practice for the treatment of musculoskeletal disorders. Our results demonstrate a transient beneficial effect of acute exposure to whole body vibration on the IVD. Furthermore, we demonstrate that this response is both frequency-dependent and tissue autonomous (Chapter 5). In follow up studies, we demonstrated that repeated exposure to vibration resulted in dramatic catabolic effects leading to degeneration of the IVD. These detrimental effects were also detected in tissues of the knee joint, mediated in both joints by the activation of matrix metalloproteinases (Chapter 6). In summary, this work uses novel mouse models to provide insight to intervertebral disc development, degeneration and the response of the IVD to mechanical loading.
Recommended Citation
McCann, Matthew R., "Mouse Models of Intervertebral Disc Development, Degeneration and Mechanical Loading" (2014). Electronic Thesis and Dissertation Repository. 2623.
https://ir.lib.uwo.ca/etd/2623