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Publication The Role of the Endocannabinoid System in a Hibernator Model of Disuse Osteoporosis Resistance and the Anabolic Response to PTH Osteoporosis Treatment(2024-09) Emily CravensOsteoporosis is a disease of bone loss that affects 200 million women and results in over 8.9 million fractures annually. Determining an optimal treatment method for patients continues to be problematic because individuals exhibit unique responses to various current osteoporosis treatments. For instance, some individuals are nonresponsive to a specific osteoporosis treatment, such as parathyroid hormone (PTH). There is a strong clinical need for alternative osteoporosis treatments, as well as diagnostic methods that quickly and accurately evaluate an individual’s response to an osteoporosis medication for more effective treatment. Hibernators pose an intriguing model for osteoporosis treatment because they do not experience expected bone loss with age or from extended periods of disuse. However, the mechanism used by hibernators to prevent bone loss remains unknown. One potential mechanism hibernators may use to mitigate bone loss is the endocannabinoid system. Endocannabinoids are signaling molecules found throughout the body and are known to play a critical role in homeostasis of bone metabolism. This dissertation explores the influence of the endocannabinoid system in the regulation of bone metabolism of a hibernator through assessing: 1) Seasonal changes in endocannabinoid concentrations in bone and other metabolically relevant tissues of a hibernator, the yellow-bellied marmot; 2) Neural influence of the endocannabinoid system on bone metabolism though neurectomy in hibernating and active marmots; 3) Contribution of cannabinoid receptor CB2 on preventing bone loss in the hibernator, golden mantled ground squirrel through inverse agonism of CB2. This dissertation also examines the diagnostic efficacy of circulating endocannabinoid concentrations as biomarkers for bone loss during osteoporosis development, and for predicting long-term responsiveness to PTH osteoporosis treatment, longitudinally in vivo in a rat ovariectomy osteoporosis model. Furthermore, CB2 inverse agonism was utilized in this model to better define the role of the endocannabinoid system in PTH osteoanabolism. Endocannabinoid concentrations were quantified using targeted mass spectrometry and bone properties evaluated using micro-computed tomography. Notably, marmots exhibited substantial seasonal changes in the endocannabinoid system that may beneficially influence regulation of energy metabolism and mitigate bone loss with inactivity. Ovariectomized rat findings indicated that endocannabinoids may be efficacious as a biomarker for treatment response.