Author ORCID Identifier
0000-0001-8651-2047
Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Clinical and Translational Sciences
First Advisor
Henry J. Donahue
Abstract
Both age-related and disuse-related bone loss result in decreases in bone mineral density, cortical thickness, and trabecular thickness and connectivity. Disuse induces physiological changes in bone similar to those seen with aging. This study compared age- and disuse-related bone loss using C57BL/6J mice of various ages that were hind-limb unloaded (HLU). In male and female mice, HLU induced a bone phenotype between those of 6-month-old and 22-month-old control mice. Gene analysis suggested that HLU leads to mitochondrial dysfunction, while aging primarily downregulates cell cycle processes. Although, the specific response to HLU appeared to be dependent on age. The study identified the "Senescence Pathway" as significantly affected by HLU in younger mice but not in older mice on RNA sequencing, however key markers of senescence were not observed in histology or qPCR.
Given the ambiguity of senescence presentation in HLU, the effectiveness of eliminating senescent cells in preventing disuse-induced bone loss was determined. Using both a transgenic model, p16-INK-ATTAC, and a senolytic cocktail, dasatinib and quercetin, the study found no significant changes in bone parameters, biomechanical properties, or gene expression. In conclusion, senescence does not likely play a key role in establishing disuse-induced bone loss in young adult mice during a three-week period of disuse.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
7-23-2024