Abstract

Osteoarthritis (OA) is a common and incapacitating joint disease beginning with breakdown of articular cartilage and extending into subchondral bone. At present, the processes through which the disease occurs are poorly understood, and interventions are limited to pain relief and eventual joint replacement. OA is commonly associated with obesity and corresponding pathologies, and as OA is demonstrably not a product of passive erosion of cartilage over time or under increased loads there must needs be some other mechanistic link between the two conditions. We hypothesize that the production of ceramides, a hallmark of the insulin resistance syndrome underlying many obesity-related conditions, acts to induce OA through its pro-inflammatory and pro-apoptotic activities, as well as directly inhibiting intracellular mediators of cartilage production and homeostasis. We demonstrate in Wistar rats that a high-fat, high-sugar (HFHS) diet successfully induces OA and that downregulation of ceramide synthesis through intraperitoneal myriocin administration does not prevent this degradation, and that myriocin in conjunction with a standard chow diet actually induces OA. Alteration in OA biomarkers in this study are discussed. We then tested the efficacy of a topical regimen of wogonin, an anti-inflammatory, anti-oxidative, and potentially analgesic compound in a surgical destabilization model (DMM) of OA in mice and demonstrate its disease modifying anti-OA properties. We further test the efficacy of this compound on the HFHS model previously established and find it successfully ameliorated the morphology and biomarker changes associated with OA; based on this data we hypothesize that inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is the most relevant physiological target of wogonin in a HFHS-induced OA model. Lastly and separately, we seek to clarify conflicting data regarding secondhand smoke (SHS), which observational studies suggest having either deleterious or beneficial effects to preexisting OA. In the first controlled study on the subject we model we demonstrate in a murine DMM model that SHS accelerates cartilage degradation and patterns of biomarker expression characteristic of OA, eliminating the question of any potential benefits of SHS to articular cartilage.

Degree

PhD

College and Department

Life Sciences

Rights

https://lib.byu.edu/about/copyright/

Date Submitted

2022-03-30

Document Type

Dissertation

Handle

http://hdl.lib.byu.edu/1877/etd12086

Keywords

osteoarthritis, insulin resistance, metabolic syndrome, type II diabetes mellitus, ceramide, wogonin, oxidative signaling, inflammation

Language

english

Included in

Life Sciences Commons

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