Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Collaborative Specialization

Musculoskeletal Health Research

Supervisor

Seguin, Cheryle A.

Abstract

Lower back pain (LBP) is one of the most common conditions worldwide, yet, current therapeutics are limited to symptomatic relief and do not directly treat the underlying cause of pain. This is largely due to an incomplete understanding of the biological pathways and tissues involved in LBP. While many tissues appear to be involved, intervertebral disc (IVD) degeneration is believed to be a major contributor.

The main aim of this thesis was to characterize the role of two environmental risk factors, mechanical loading and obesity, in the initiation of IVD degeneration and associated pain using the mouse as a preclinical model. We first investigated the effects of mechanical loading, specifically whole-body vibration (WBV), on joint health. In contrast to previous findings in CD-1 mice, we show that WBV delivered using parameters that model those used clinically does not affect joint health in C57BL/6 mice . These findings suggest that the response of joint tissues to WBV may vary in a strain-specific manner.

We next evaluated the impact of diet-induced obesity on IVD degeneration and associated pain. Ten-week-old male C57BL/6N mice were fed either a control, high-fat, or western diet for 12, 24 or 40 weeks. At endpoint, mice were assessed for behavioral indicators of pain and histological and molecular analyses were carried out on joint and neural tissues. We demonstrated that diet-induced obesity accelerates IVD degeneration; however, pain-related behaviors precede histological joint damage.

Finally, we examined the role of peroxisome proliferator-activated receptor delta (PPARδ) as a potential mediator of IVD degeneration. We confirmed that PPARδ was expressed and functionally active in the IVD and used male and female, cartilage-specific Ppard knockout (Ppard KO) mouse to assess age- and obesity-associated IVD degeneration. Loss of PPARδ appeared to be protected against age-associated IVD degeneration; however, this protective effect was not observed with obesity-induced IVD degeneration or knee osteoarthritis.

Overall, this data highlights the complex interactions between modifiable and non-modifiable risk factors as drivers of IVD degeneration and associated back pain. Furthermore, these studies highlight the importance of including sex as a biological variable and assessing pain and IVD degeneration, as they do not always correlate.

Summary for Lay Audience

Lower back pain (LBP) is one of the most common causes of disability worldwide, yet current treatments are limited to pain relief and do not directly treat the underlying cause of pain. This is largely due to an incomplete understanding of what tissues contribute to LBP and why pain occurs. Large-scale association studies in humans have identified several risk factors for the development of LBP including age, genetics, mechanical loading and obesity; however, how and why they cause the pain is largely unknown.

While many tissues appear to be involved in LBP, intervertebral disc (IVD) degeneration is believed to be a major contributor in many cases. IVDs are specialized joints located between the vertebrae in the spine that act as shock absorbers, helping to dissipate mechanical loading. Degeneration is a progressive biological process that results in the functional failure of the tissue and can result in pain. This research was designed to investigate the impact of mechanical loading, specifically whole-body vibration (WBV), and obesity on IVD degeneration and associated pain using the mouse as a model system. Furthermore, we investigate a potential biological mediator to explain how obesity impacts IVD degeneration and associated pain.

In our first study we demonstrate that the response of joint tissues to WBV vary based on genetic background of the animals. In our second study we demonstrated that diet-induced obesity does accelerate IVD degeneration and pain-related behavior in a mouse model; however, pain related behaviors precede structural IVD damage. Lastly, we assessed a potential biological mediator of IVD degeneration - peroxisome proliferator activated receptor delta (PPARδ) – in aging and obesity. Using mice that had the PPARδ gene deleted in joint tissues, we showed that loss of PPARδ protected against age-associated IVD degeneration; however, this protective effect was not observed with obesity-induced IVD degeneration.

Taken together, this thesis highlights the complex interactions between mechanical loading and obesity as drivers of IVD degeneration and associated back pain. Furthermore, these studies highlight the importance of including sex as a biological variable and assessing pain and IVD degeneration, as they do not always correlate.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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