Doctor of Philosophy
Dr. Frank Beier
Osteoarthritis (OA) affects 1 in 10 Canadians and is a leading cause of mobility disability worldwide. This condition is characterized by cartilage degeneration, subchondral bone damage and inflammation of the synovium, resulting in pain and joint failure. No treatments exist to stop the progression of this disease, and its underlying molecular mechanisms remain largely unknown. We previously identified the peroxisome proliferator activated receptor (PPAR) nuclear receptor pathway as altered in OA cartilage. In-vitro studies identified PPARd as a promoter of catabolic activity in chondrocytes, providing the foundation for my overarching hypothesis that PPARd inhibition is protective in OA.
I commenced my thesis by generating Ppard cartilage-specific knockout mice to investigate the role of this gene in skeletal development. I evaluated the anatomy, morphology, and cellular organization of the skeleton, long bones and growth plate through histological techniques and concluded that there were no congenital abnormalities predisposing these mice to OA. I next compared the progression of disease severity between Ppard KO mice and WT controls after destabilization of medial meniscus surgery to induce post-traumatic osteoarthritis (PTOA). After histopathological assessment, I found that mice lacking PPARd were significantly protected from cartilage damage and displayed decreased cartilage matrix breakdown in lesioned areas.
Subsequently, I evaluated pharmacological inhibition of PPARd in PTOA in rats. I discovered that PPARd inhibitors prevent behavioural modifications associated with OA development and pain. However, their effects on structural progression of OA remains inconclusive and more stringent quantitative methods are needed to assess these differences.
Lastly, I examined global gene expression through microarray analysis of chondrocytes treated with a PPARd agonist. I discovered that genes induced were primarily involved in lipid metabolism, which translated into functional changes in lipid metabolism, such as significantly decreased cellular triglycerides. Mediators of oxidative stress were also identified, and Txnip, an inhibitor of anti-oxidant thioredoxin, was significantly elevated in response to PPARd activation. Immunohistochemistry revealed increased TXNIP staining in OA cartilage, but substantially less in cartilage of Ppard KO mice.
Overall, these data demonstrate a novel role for PPARd in Osteoarthritis. My data support my hypothesis that PPARd inhibition is protective in OA.
Ratneswaran, Anusha, "Peroxisome Proliferator Activated Receptor Delta in Osteoarthritis" (2016). Electronic Thesis and Dissertation Repository. 3853.
Available for download on Wednesday, July 01, 2020