Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Anatomy and Cell Biology

Collaborative Specialization

Musculoskeletal Health Research

Supervisor

Penuela, Silvia

2nd Supervisor

Beier, Frank

Co-Supervisor

Abstract

Pannexin 3 (PANX3), is a glycoprotein that oligomerizes to form mechano-sensitive channels expressed in musculoskeletal tissues, and has been identified as a potential target for the treatment of obesity and osteoarthritis (OA). Obesity and OA are two of the most prevalent diseases worldwide, leading to disability and even death. These conditions are thought to originate from a complex interaction between genetics, aging, sex, and modifiable lifestyle factors, such as exercise. Investigating the interactions between genetic and exercise may provide a more comprehensive, context-specific understanding of gene function. This thesis aimed to understand the interactions between PANX3 and exercise interventions on relevant factors of obesity, metabolism, inflammation, and OA. Male and female wildtype (WT) and Panx3 knockout (KO) mice were bred, fed a standard chow diet or a high fat diet, and randomized to either no exercise or forced treadmill running daily for 6 weeks at either 24 weeks (young adult) or 18 months of age (aged). We discovered that, specifically in male mice, Panx3 deletion results in substantially lower body weights because of less fat mass and increased lean mass. This change in body composition was similar to that achieved by 6 weeks of forced treadmill running in WT mice. Additionally, male Panx3 KO mice had reduced inflammatory profile of their fat and muscle tissue and circulating levels of Interluekin-6. There was no additional effect of forced exercise on the body composition of Panx3 KO mice. At the knee joint, however, deleting Panx3 and forced treadmill running worked synergistically, resulting in large superficial fibrillations of the tibial cartilage and increased bone in the subchondral region. At the intervertebral discs, Panx3 KO mice had histopathological features of accelerated disc degeneration with forced treadmill running compared to sedentary WT mice. In aging, both male and female Panx3 KO mice develop spontaneous OA characterized by full thickness cartilage erosion and synovitis. This data suggests Panx3 influences fat accumulation, inflammation, and joint pathology and that these effects are dependent on the sex, age, and exercised state of the animal.

Summary for Lay Audience

Obesity and osteoarthritis (OA) are two of the most common causes of disability worldwide, and current treatments are limited to lifestyle interventions. This is largely due to an incomplete understanding of the mechanisms of these diseases. Association studies in humans have identified several risk factors for developing these diseases including sex, genetics, ageing, and lifestyle factors such as diet and physical activity. How these factors interact to cause these diseases is unknown.

Pannexin 3 (PANX3) is a protein that forms large pores in our cell membranes, that are sensitive to mechanical stress, allowing the release of signalling molecules. This signalling is necessary for normal cell function, but if dysregulated, can contribute to disease progression. In fact, PANX3 has been implicated in development of fat tissue and OA. The purpose of this research was to determine the role of PANX3 in fat accumulation, inflammation, and joint health and whether forced treadmill running influences the outcomes.

In the first study, deleting the gene encoding for PANX3 resulted in large reductions in fat mass in male mice and lower fat and muscle tissue inflammation, to the same degree as 6 weeks of forced treadmill running in mice with the PANX3 gene. In the second study, mice lacking Panx3 accumulate damage to various tissues of their joints, indicative of degeneration, and that forced treadmill running in males caused further damage of the joint surface. Lastly, in the final study, mice without Panx3 age, they develop severe tissue degeneration in the knee, indicative of OA.

Taken together, this thesis highlights the potential contribution of PANX3 to obesity and OA, and how sex, age, and exercised state of the animal influence its importance.

Creative Commons License

Creative Commons Attribution-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-No Derivative Works 4.0 License.

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