Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Physiology and Pharmacology

Collaborative Specialization

Musculoskeletal Health Research

Supervisor

Frank Beier

Abstract

Osteoarthritis is a common chronic disorder of joints which leads to the reduction of articular cartilage and pain. This research depicts the function of peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1α) in chondrocytes that maintains mitochondrial function and its role in OA pathogenesis. We analyzed the impact of the PGC1α inhibitor SR-18292 in gene expression and mitochondrial function using immature murine articular chondrocytes (IMACs) in primary culture. There was an important and marked downregulation of mitochondrial-related genes (Esrra, Nrf1, Tfam) in response to SR-18292 treatment, as indicated by quantitative real-time PCR and RNA sequencing studies. Additional fluorescence imaging showed markedly decreased mass and mitochondrial membrane potential. These findings reinforced the premise that PGC1α had a key role in maintenance of mitochondrial health in chondrocytes and that its inhibition may drive OA development.

Summary for Lay Audience

Osteoarthritis is a common disease in the joint. It's caused by the wearing of a protective cushion at the ends of bones located in a joint, causing pain and movement limitation. However, despite its prevalence, effective therapies for OA are lacking, largely because the precise biological processes driving the disease remain to be fully understood. This study aimed at the special protein PGC1α; it is known to play a critical role in the maintenance of mitochondrial health, the energy powerhouse, in cartilage.

Mitochondria are the energy suppliers for normal cellular activities; thus, any disturbance in this activity may lead to cellular damage or diseases. The study was designed to define changes happening in chondrocytes that occur when activity of PGC1α is pharmacologically inhibited by a small molecule known as SR-18292. The aim was to understand whether impairing mitochondrial function in cartilage cells contributes to the development of OA.

We treated chondrocytes from mice with SR-18292 and observed changes in gene activity and mitochondrial function. Our experiments showed that in case PGC1α is not able to work, the activity of genes responsible for the maintenance of mitochondria health drops. It means that mitochondria presented in these cells are not working properly. Subsequent experiments, using special dyes which fluoresce when they interact with healthy mitochondria, showed that both the amount and the function of the mitochondria were reduced in treated cells.

Such findings are important in the respect that they give a clearer picture of how mitochondrial dysfunction in chondrocytes may contribute to the progression of OA. An understanding of these processes allows for new opportunities for treatment. For example, it might become possible to delay or prevent the process leading to cartilage degradation in OA through therapeutic activity using PGC1α, or by improving mitochondrial function.

Overall, the current study has identified the PGC1α importance in chondrocytes to sustain cellular health and brought mitochondrial dysfunction. This possibly suggests new therapeutic interventions that focus on these basic cellular processes will be developed, leading to improved management of the disease.

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