
Thesis Format
Integrated Article
Degree
Doctor of Philosophy
Program
Physiology and Pharmacology
Collaborative Specialization
Musculoskeletal Health Research
Supervisor
Seguin, Cheryle A.
2nd Supervisor
Leung, Andrew E.
Affiliation
London Health Sciences Center
Co-Supervisor
Abstract
Low back pain is the leading cause of years lived with disability worldwide. Although the origins of back pain are poorly understood, it is often associated with the intervertebral disc (IVD). The IVDs are joints located between vertebrae of the spine, responsible for flexion and shock absorption during movement. Aging, trauma, and biological sex are all linked to IVD degeneration. There are no disease-modifying treatments for IVD degeneration.
The aims of this thesis were three-fold. The first was to characterize age-associated disc degeneration in mouse strains commonly used to study IVD degeneration (C57BL/6 and CD-1). We assessed changes associated with age, sex, and spinal regions. This work developed an atlas of IVD degeneration based on these parameters. We found distinct differences in the presentation of IVD degeneration between strains. While CD-1 mice presented with degeneration earlier than C57BL/6, male mice were more susceptible in both strains. In addition, the caudal spine was always resistant to age-associated degeneration.
Based on multiple reports of increased IVD height and decreased incidence of back pain in suspected steroid users, as well as the clinical use of testosterone injections to treat back pain we next evaluated the effects of anabolic steroids and sex hormones on the IVD. As our second aim, we used IVD explants and primary cell cultures to evaluate how sex hormones alter IVD cell biology. We demonstrated that, in a cell type-specific manner, sex hormones attenuate inflammatory gene expression and modulate cytokine release from nucleus pulposus cells.
Finally, our third aim investigated the effects of systemic testosterone injections on age- and injury-associated IVD degeneration using an in-vivo mouse model with a longitudinal study design. We confirmed that testosterone injections alter IVD biology; specifically increasing disc height index in the lower lumbar spine. However, we show that this change is likely linked to changes in the vertebral and subchondral bone. Testosterone injections also rescued the loss of disc height following injury in the tail.
Overall, we showed that sex hormones alter IVD biology and warrant further investigation to explore their benefits and limitations as potential disease-modifying treatments for disc degeneration.
Summary for Lay Audience
The Global Burden of Disease study reported that low back pain is the leading cause of years lived with disability worldwide, with a lifetime prevalence of up to 84%. The occurrence of back pain increases with age; men are at higher risk for back pain than women until the fifth decade of life corresponding with the onset of menopause, after which women are more likely to experience back pain than men. Though back pain is complex with many causes, degeneration of the spinal joints termed intervertebral discs (IVDs) is associated with ~ 40% of cases.
This research was inspired by clinical observations of a dramatic increase in the size of IVDs in the lower back of competitive athletes and suspected anabolic steroid users. This finding is completely unexpected since IVD size decreases with age. The main objective of this thesis was to determine if sex hormones, such as those used found in steroids or received through hormone replacement therapy, would influence IVD biology.
We first compared age-associated IVD degeneration in different strains of mice commonly used in preclinical studies comparing changes over time based on age, sex, and anatomical regions. We showed that IVD degeneration is dependent on age and influenced by strain, anatomical location, and biological sex.
Second, we determined how sex hormones influence IVD biology using IVD tissues and primary cell cultures. These models were used to determine how sex hormones influence healthy cells, as well as cells within an inflammatory environment. Our research showed that sex hormones dampened the effects of inflammation in intervertebral disc cells.
Lastly, we combined models of both age and injury-induced disc degeneration in mice to study the effects of doses of testosterone modeling steroid use. Testosterone had some beneficial effects, increasing IVD size both in aging mice and preventing loss following injury, but these effects were associated with changes to the bones of the spine.
Taken together, this work has explored the effects of sex hormones on intervertebral disc health and form the basis for clarifying beneficial and detrimental effects.
Recommended Citation
Hutchinson, Jeffrey L., "Investigating the Role of Sex Hormones in the Intervertebral Disc" (2024). Electronic Thesis and Dissertation Repository. 10594.
https://ir.lib.uwo.ca/etd/10594