Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Supervisor

Beier, Frank

Abstract

Osteoarthritis (OA) is a heterogeneous and multifactorial degenerative disease characterized by cartilage degradation in the joint. Available treatment options target symptoms but do not address the underlying issue of joint tissue degeneration. A better understanding of the molecular mechanisms maintaining cartilage health is essential for developing novel therapeutic strategies. Previous studies have shown the nuclear receptor Liver X Receptor (LXR) to possess protective roles against cartilage breakdown in OA, however the underlying mechanisms behind this process remain unknown. Since LXR regulates transcription by forming obligate heterodimers with another nuclear receptor, the Retinoid X Receptor (RXR), I hypothesized that LXR and RXR regulate cartilage development, maturation and lipid homeostasis.

The first study of this thesis investigated the effect of LXR activation on chondrocyte differentiation in order to elucidate the molecular mechanisms behind LXR’s protection against OA. Three different chondrogenic culture systems were treated with the specific LXR agonist, GW3965, and it was found that LXR activation suppressed chondrocyte hypertrophy, in part through the delay of cell-cycle exit and consequent retention of chondrocyte proliferation.

To further identify the intracellular changes that occur to elicit this suppression in hypertrophy, I conducted microarray analysis on growth plate chondrocytes treated with GW3965 in my second study. LXR activation caused differential regulation of various genes involved in lipid metabolism, including central players mediating cellular cholesterol efflux. These findings demonstrate a potential link between LXR’s role in lipid metabolism and the differentiation of developing chondrocytes.

Lastly, to gain insight into LXR and RXR’s transcriptional effects in articular chondrocytes, I conducted microarray analysis on immature murine articular chondrocytes (IMACs) treated with either a LXR or RXR agonist. Both LXR and RXR activation differentially regulated cellular lipid metabolism. However, they appear to exert opposing effects on cellular oxidative stress response and maintenance of extracellular matrix (ECM) homeostasis, suggesting contrasting roles in OA progression.

Collectively, these data demonstrate that LXR and RXR regulate various cellular mechanisms involved in metabolic homeostasis of both growth plate and articular chondrocytes. Deeper understanding of nuclear receptor function in chondrocytes will contribute to better understanding of the molecular pathways controlling cartilage health and disease.

Available for download on Thursday, December 12, 2019

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