<p>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.</p><p><br></p><p>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.</p><p><br></p><p>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.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/12272285 |
| Date | 08 May 2020 |
| Creators | Kara A Negrini (8102609) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY-NC-SA 4.0 |
| Relation | https://figshare.com/articles/Novel_Extrinsic_and_Intrinsic_Factors_Mediating_Osteoarthritis/12272285 |
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