Date of Award

Spring 5-15-2022

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type



Osteoarthritis (OA) is a highly prevalent and debilitating chronic disease that causes joint degradation, leading to poor quality of life and difficulty navigating even simple day to day tasks. OA is characterized primarily by cartilage degeneration, as well as subchondral changes and overall joint dysfunction, though there are currently no disease modifying therapeutics for the condition, only approaches to alleviate symptoms or ultimately, joint replacement surgery. Both biomechanical and molecular factors contribute to OA initiation and progression, with studies over the years displaying that inflammation is an important component of disease pathophysiology. Pro-inflammatory cytokines such as IL-1β and TNF-α are elevated in OA joints and have been shown to drive the expression of catabolic genes, which can cause cartilage loss if it exceeds the anabolic capacity of chondrocytes. Hence, there is great need to fill in the knowledge gap to enable development of therapeutics that reduce catabolic activity and/or increase anabolic activity to regenerate cartilage. In order to develop novel therapeutics for the treatment of OA, it is necessary to better understand the pathophysiological changes that occur in OA chondrocytes. The overall goal of this dissertation is to better understand the cellular changes induced by inflammation in chondrocytes and the role chondrocytes play in modulating cartilage degradation. The first aim of this dissertation is focused on understanding the role of NF-κB activation in the pathogenesis of OA. NF-κB pathway is one of the principle inflammatory response pathways activated by inflammatory cytokines. We begin by displaying that NF-κB signaling is chronically activated in OA chondrocytes and is a driver of cartilage degradation, identifying chondrocytes as an ideal target for therapeutics. Furthermore, we display that NF-κB activation can lead to increased cellular senescence, which can further promote a chronic inflammatory state via increased senescence-associated secretory phenotype (SASP) factors production. We then display chondrocytes may regulate osteoclast-mediated bone breakdown and that bone matrix particles are potent inflammatory mediators that have not been previously characterized in OA but may be highly damaging. Finally, we demonstrate that inhibition of NF-κB is protective against OA. The second aim of this dissertation then focuses on understanding downstream consequences of NF-κB activation, since systemic NF-κB inhibition can be harmful. We observed that chondrocytes under inflammatory conditions undergo metabolic reprogramming, with increased aerobic glycolysis and decreased TCA cycle/oxidative phosphorylation. This metabolic reprogramming was then targeted using FX11, a small molecule inhibitor of lactate dehydrogenase A (LDHA) which we show inhibits the inflammatory response to IL-1β treatment in an NF-κB-independent manner. We then show that this effect is due to a decrease in the expression of IκB-ζ, an atypical IκB that promotes inflammation, in a post-transcriptional manner, to regulate the expression of inflammatory response changes implicated in cartilage degradation. Mechanistically, this occurs through inhibition of LDHA-mediated reactive oxygen species (ROS) amplification, a novel function of LDHA during pathological conditions to promote oxidative stress. Our work suggests that LDHA can promote the donation of electrons from NADH to oxygen-containing compounds to form free radicals, an effect which is blocked by FX11, an NADH analogue. Finally, we display that IκB-ζ is a redox sensitive protein whose stability is regulated by oxidative stress, preventing its targeting to the proteasome. The third aim of this dissertation seeks to look at other aspects of metabolism and their relationship to the inflammatory response. We show for example that mitochondrial electron transport chain (ETC) activity is pathological in chondrocytes, and can be targeted to reduce the inflammatory response. We also display that NAMPT, the rate limiting step in NAD+ synthesis, is a pro-catabolic factor during disease states, likely through regulation of NAD+-dependent enzyme activity and cellular metabolism. We finally display that glutamine is an important nutrient for chondrocytes, and that glutamine deprivation can prevent inflammation, likely due to altered anaplerotic reactions and a shift away from the production of pro-inflammatory metabolites. Overall, this section seeks to highlight some examples that confirm that metabolism and inflammation are intertwined and highly co-regulatory. This work as a whole advances the understanding of the mechanisms that are involved in modulating the inflammatory and catabolic responses of chondrocytes through NF-κB-dependent and independent systems. It further provides an example of metabolic changes as a viable therapeutic target for the prevention of cartilage degradation and mechanistically describes this relationship, hopefully opening the doors for further research into the metabolic intricacies of chondrocytes during health and human disease.


English (en)

Chair and Committee

Yousef Abu-Amer

Committee Members

Steven Teitelbaum


Update embargo

Available for download on Friday, May 20, 2112

Included in

Biochemistry Commons