Energy metabolism and mechanotransduction in osteoarthritic chondrocytes: targeted metabolic profiling and flux analysis

dc.contributor.advisorChairperson, Graduate Committee: Ronald K. June IIen
dc.contributor.authorErdogan, Ayten Ebruen
dc.contributor.otherThis is a manuscript style paper that includes co-authored chapters.en
dc.date.accessioned2025-02-03T20:56:32Z
dc.date.issued2023en
dc.description.abstractOsteoarthritis (OA) is a prevalent and debilitating disease that affects hundreds of millions people worldwide. One of OAs major consequences is the degradation of articular cartilage, leading to joint pain, stiffness, and loss of function. Currently, there is no treatment for OA. The existing interventions are mostly for suppressing the symptoms: physical therapy, anti-inflammatories, and pain management. The last resort is total joint replacement, which has long-term consequences especially for early-onset OA patients. Thus, researchers are focusing on understanding this complex disease and its molecular components to develop better treatments. Chondrocytes, the sole cell type in articular cartilage, play a crucial role in maintaining tissue homeostasis and responding to mechanical stimuli via synthesis of key structural components like collagen. However, the intracellular pathways underlying chondrocyte mechanotransduction are not fully understood, especially those related to central carbon metabolism. This thesis uses 13C isotopic labeling to trace carbon sources and downstream metabolites related to energy metabolism in vitro. Primary human articular chondrocytes from OA patients exposed to labeled glucose and glutamine, and their global and targeted metabolite profiles are assessed. The results show how both glucose and glutamine utilization as carbon sources flows through the TCA cycle. This work also develops a comprehensive model of mammalian carbon metabolism in OA primary human chondrocytes. The model integrates energy metabolism, amino acid synthesis, and transport reactions contributing to Collagen-II and Collagen-VI production. Using flux balance analysis (FBA), trade-offs between Collagen-II and Collagen-VI synthesis are evaluated based on ATP and carbon source requirements under different oxidative stress conditions. Then, these model predictions are presented with experimental data obtained from OA chondrocytes subjected to shear and compressive mechanical stimulation, which can be integrated in the model later on. These data shed new light on metabolism of primary OA chondrocytes and provides insight into potential therapeutic targets for OA intervention.en
dc.identifier.urihttps://scholarworks.montana.edu/handle/1/19129
dc.language.isoenen
dc.publisherMontana State University - Bozeman, College of Engineeringen
dc.rights.holderCopyright 2023 by Ayten Ebru Erdoganen
dc.subject.lcshOsteoarthritisen
dc.subject.lcshCartilage cellsen
dc.subject.lcshMetabolismen
dc.subject.lcshCellular signal transductionen
dc.subject.lcshCarbonen
dc.titleEnergy metabolism and mechanotransduction in osteoarthritic chondrocytes: targeted metabolic profiling and flux analysisen
dc.typeThesisen
mus.data.thumbpage14en
thesis.degree.committeemembersMembers, Graduate Committee: Jeffrey Heys; Ross Carlson; Sarah L. Codden
thesis.degree.departmentChemical & Biological Engineering.en
thesis.degree.genreThesisen
thesis.degree.nameMSen
thesis.format.extentfirstpage1en
thesis.format.extentlastpage149en

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