Doctor of Philosophy
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.
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Available for download on Wednesday, June 24, 2026