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Browsing by Author "Priddy, Carlie"
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Item Mechanotransduction in Living Bone: Effects of the Keap1-Nrf2 Pathway(2019-08) Priddy, Carlie; Li, Jiliang; Dai, Guoli; Wallace, Joseph M.The Keap1-Nrf2 pathway regulates a wide range of cytoprotective genes, and has been found to serve a protective and beneficial role in many body systems. There is limited information available, however, about its role in bone homeostasis. While Nrf2 activation has been suggested as an effective method of increasing bone mass and quality, there have been conflicting reports which associate Keap1 deficiency with detrimental phenotypes. As Keap1 deletion is a common method of Nrf2 activation, further study should address the impacts of various methods of regulating Nrf2 expression. Also, little research has been conducted on the specific pathways by which Nrf2 activation improves bone quality. In this study, the effects of alterations to Nrf2 activation levels were explored in two specific and varied scenarios. In the first experiment, moderate Nrf2 activation was achieved via partial deletion of its sequestering protein, Keap1, in an aging mouse model. The hypothesis tested here is that moderate Nrf2 activation improves bone quality by affecting bone metabolism and response to mechanical loading. The results of this first experiment suggest a subtle, sex-specific effect of moderate Nrf2 activation in aging mice which improves specific indices of bone quality to varying degrees, but does not affect loading-induced bone formation. It is likely that the overwhelming phenotypic impacts associated with aging or the systemic effects of global Keap1 deficiency may increase the difficulty in parsing out significant effects that can be attributed solely to Nrf2 activation. In the second experiment, a cell-specific knockout of Nrf2 in the osteocytes was achieved using a Cre/Lox breeding system. The hypothesis tested here is that osteocyte-specific deletion of Nrf2 impairs bone quality by affecting bone metabolism and response to mechanical loading. The results of this experiment suggest an important role of Nrf2 in osteocyte function which improves certain indices of bone quality, which impacts male and female bones in different 7 ways, but did not significantly impact loading-induced bone formation. Further studies should modify the method of Nrf2 activation in an effort to refine the animal model, allowing the effects of Nrf2 to be isolated from the potential systemic effects of Keap1 deletion. Future studies should also utilize other conditional knockout models to elucidate the effects of Nrf2 in other specific cell types.Item The role of the Nrf2/Keap1 signaling cascade in mechanobiology and bone health(Elsevier, 2021-11-22) Priddy, Carlie; Li, Jiliang; Biology, School of ScienceIn conjunction with advancements in modern medicine, bone health is becoming an increasingly prevalent concern among a global population with an ever-growing life expectancy. Countless factors contribute to declining bone strength, and age exacerbates nearly all of them. The detrimental effects of bone loss have a profound impact on quality of life. As such, there is a great need for full exploration of potential therapeutic targets that may provide antiaging benefits and increase the life and strength of bone tissues. The Keap1-Nrf2 pathway is a promising avenue of this research. The cytoprotective and antioxidant functions of this pathway have been shown to mitigate the deleterious effects of oxidative stress on bone tissues, but the exact cellular and molecular mechanisms by which this occurs are not yet fully understood. Presently, refined animal and loading models are allowing exploration into the effect of the Keap1-Nrf2 pathway in a tissue-specific or even cell-specific manner. In addition, Nrf2 activators currently undergoing clinical trials can be utilized to investigate the particular cellular mechanisms at work in this cytoprotective cascade. Although the timing and dosing of treatment with Nrf2 activators need to be further investigated, these activators have great potential to be used clinically to prevent and treat osteoporosis.