File(s) under embargo
until file(s) become available
Novel Extrinsic and Intrinsic Factors Mediating Osteoarthritis
Osteoarthritis (OA) is a leading cause of disability globally, with higher incidence in older people and lower socioeconomic status populations. The challenges health care systems face with management of the disease highlights the importance of OA research. Many studies examine possible risk factors of knee and hip OA including obesity, smoking, and alcohol consumption. Findings support that while obesity increases risk of knee OA, smoking is not a major risk factor. These extrinsic factors are, however, associated with lower socioeconomic status, and also with anxiety and depression disorders. Up to 30% of patients with chronic knee OA have described psychological stress and decreased quality of life due to debilitating pain, but the effects of psychological stress on development of knee OA has not been described.
At the cellular level, mechanosensitive cation channels in cartilage and bone, are involved with OA, but studies looking specifically at synovium and joint capsule are limited. Transient receptor potential (TRP) channels are upregulated in joint capsule in end-stage primary shoulder OA. We were unable to identify any previous studies evaluating Piezo channel expression in musculoskeletal soft tissues, but Piezo channel antagonism reduces chondrocyte death after mechanical injury. These findings suggest channels may help regulate joint responses to repetitive loading during training or work while also contributing to protective mechanisms within the musculoskeletal system. The overall objective of this research was to investigate factors that impact OA development or the disease phenotype. Two studies evaluated the following aims: 1) demonstrate the influence of chronic psychological stress on knee OA and overall systemic health, and 2) characterize the role of mechanosensitive channels in the joint capsule in OA. The first study used a mouse chronic social defeat model paired with destabilization of the medial meniscus (DMM) surgery to create a social stress scenario during OA development. We hypothesized chronic social defeat would exacerbate knee OA structural changes and systemic inflammation. The second study aimed to explore the role of mechanosensitive channels in joint capsule during OA development in the equine. Immunohistochemistry was performed on forelimb fetlock joint capsule from horses with varying degrees of lameness to first identify TRP and Piezo channel expression. Next, fibroblasts were isolated from the tissue to determine channel activity. We hypothesized that TRP and Piezo channels are required for normal homeostasis, but are dysregulated in OA and dysregulation contributes to fibrosis of the joint capsule. Joint capsule fibrosis leads to joint stiffening and reduced range of motion, two of the cardinal signs of OA.
The results of the first study showed OA was induced to a similar extent in both groups of mice that underwent DMM surgery. While anxiety- and depressive-like behaviors were exhibited by mice that underwent chronic social defeat episodes, unexpectedly, the majority of systemic inflammatory markers were not worse in mice with DMM and chronic social defeat compared to DMM alone. We were also able to show TRP and Piezo channel expression in one normal dorsal and palmar fetlock joint capsule sample, however, COVID-19 prevented further investigation. With our results we were able to conclude that while chronic social stress influences development of OA, in the current experiments, neither systemic inflammation nor structural signs of knee OA were worse with chronic social stress. We hope that exploration of OA through these two studies will help us understand how the disease contributes to overall systemic dysfunction while also providing a baseline for future development of TRP and Piezo channel modulators to prevent joint pathologies.