Pannexin3 in exercise, obesity, and osteoarthritis
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.