Investigating the Role of Sex Hormones in the Intervertebral Disc

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.