Characterization of metabolic changes in osteoarthritis using global metabolomic profiling

Abstract

Osteoarthritis 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.