DOI
https://doi.org/10.25772/6MQD-3174
Defense Date
2021
Document Type
Thesis
Degree Name
Doctor of Philosophy
Department
Biomedical Engineering
First Advisor
Barbara Boyan
Second Advisor
Zvi Schwartz
Third Advisor
John Ryan
Fourth Advisor
Christopher Lemmon
Fifth Advisor
Hu Yang
Abstract
Over 32.5 million adults in the United States and 300 million worldwide have osteoarthritis (OA). To date, there are no disease-modifying therapeutics, only strategies to slow OA progression through pain management, regenerative medicine approaches, and ultimately joint replacement.
On a microscale, a phenotypic shift of the normally quiescent articular chondrocytes leads to aberrant expression of pro-inflammatory and catabolic pathways, which are hypothesized to contribute to OA progression. Of note, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and WNT/β-catenin signaling are key players disrupting cartilage homeostasis and driving inflammatory pathway activation. These pathways become dysregulated and form a positive feedback loop, increasing their own production and that of other inflammatory cytokines such as prostaglandin E2; matrix-degrading proteases, including a disintegrin and metalloproteinase with thrombospondin motifs-4 and 5 and matrix metalloproteinase 1, 3 and 13. The ability to interrupt these pathways could provide treatment options for OA. The central hypothesis of this thesis was that IL-1β, TNF-α, and WNT/β-catenin signaling drive OA progression.
Previous research indicated that 24R,25 dihydroxyvitamin D3 prevents IL-1β-stimulated signaling. Specific aim 1 determined whether treatment with 24R,25-dihydroxyvitamin D3 prevents OA progression in vivo. Specific aim 2 determined if microRNA-122 and microRNA-451 controlled OA progression in vitro and how these microRNAs interact with the IL-1β, TNF-α, and WNT/β-catenin signaling pathways. Specific aim 3 investigated treating OA in vivo with microRNA-122 or a microRNA-451 inhibitor.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
8-11-2021