Chairperson, Graduate Committee: Ronald K. June IICarlson, Alyssa KayRachel A. Rawle, Erik Adams, Mark C. Greenwood, Brian Bothner and Ronald K. June were co-authors of the article, 'Application of global metabolomic profiling of synovial fluid for osteoarthritis biomarkers' in the journal 'Biochemical and biophysical research communications' which is contained within this thesis.Rachel A. Rawle, Cameron W. Wallace, Erik Adams, Mark C. Greenwood, Brian Bothner and Ronald K. June were co-authors of the article, 'Global metabolomic profiling of human synovial fluid for rheumatoid arthritis biomarkers' in the journal 'Clinical and experimental rheumatology' which is contained within this thesis.Rachel A. Rawle, Cameron Wallace, Ellen Brooks, Erik Adams, Mark C. Greenwood, Merissa Olmer, Martin K. Lotz, Brian Bothner and Ronald K. June were co-authors of the article, 'Characterization of osteoarthritis phenotypes in human synovial fluid using global metabolomic profiling' submitted to the journal 'Arthritis and rheumatology' which is contained within this thesis.Rachel A. Rawle, Erica Barboza, Albert Batushansky, Timothy M. Griffin, Brian Bothner and Ronald K. June were co-authors of the article, 'In vivio mechanotransduction: effect of acute exercise on the metabolomic profiles of mouse synovial fluid' submitted to the journal 'Journal of biomechanics' which is contained within this thesis.Rachel A. Rawle, Erin Hutchison, Joanna Hudson, Brian Bothner, Timothy M. Griffin and Ronald K. June were co-authors of the article, 'The effect of long-term voluntary exercise on the metabolomic profiles of synovial fluid from high-fat diet-induced obese mice' submitted to the journal 'Arthritis and rheumatology' which is contained within this thesis.Dissertation includes one article of which Alyssa Kay Carlson is not the main author.2020-02-262020-02-262018https://scholarworks.montana.edu/handle/1/15828Osteoarthritis affects over 250 million individuals worldwide. It is a disease of the whole joint, exhibiting heterogenous pathology, and a multifactorial etiology consisting of obesity and joint trauma as important risk factors. This heterogenous nature contributes to the disparity in symptom presentation and response to treatments, presenting challenges for diagnosis and the development of targeted therapies for osteoarthritis phenotypes. Therefore, the goals of this work were to (1) enhance our understanding of osteoarthritis as a heterogenous disease for improved early diagnosis and (2) evaluate the interaction between osteoarthritis risk factors and therapeutic interventions. Because osteoarthritis and its risk factors are associated with aberrant metabolism, liquid chromatography-mass spectrometry-based global metabolomic profiling was employed to investigate changes in small molecules in response to osteoarthritis, risk factors, and therapeutic interventions. The first area of research focused on osteoarthritis diagnosis. The results show that global metabolomic profiling of human osteoarthritic synovial fluid is capable of identifying candidate biomarkers of osteoarthritis and classifying donors into subgroups representative of metabolic phenotypes. Metabolic phenotypes include structural deterioration, oxidative stress, and/or inflammation. The second area of research focused on osteoarthritis risk factors and therapeutic interventions. We investigated the effects of acute exercise in mouse synovial fluid to provide insight into exercise as a nonpharmacologic mechanobiology-based intervention prescribed for osteoarthritis. We found that acute exercise may have beneficial effects in maintaining overall joint health. We expanded on exercise as a nonpharmacologic treatment by investigating the effects of long-term exercise in an obesity-associated osteoarthritis mouse model. Long-term exercise did not exacerbate osteoarthritis in the knee joints of obese mice but did abrogate some obesity-induced metabolic perturbations in the synovial fluid. In addition, a pharmacologic intervention was investigated in posttraumatic osteoarthritis. Inhibition of early response genes by a Cdk9 inhibitor immediately after joint trauma was also capable of reversing a portion of injury-induced metabolic perturbations in whole joints of injured mice. Overall, this work demonstrates that global metabolomic profiling has potential for biomarker discovery and classifying patients into metabolic phenotypes. It also demonstrates the potential for exercise and inhibition of early response genes as therapeutic interventions for obesity-associated and post-traumatic osteoarthritis.enArthritisDiagnosisTherapeuticsPhenotypeMetabolismMass spectrometryDissertationCopyright 2018 by Alyssa Kay Carlson