Metabolomic Profiling of a Novel In Vitro Model of Meniscal Tears
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Background- The menisci act as one of the main stabilizing and load distributing structures in the knee joint. They are composed mostly of structured type 1 collagen, proteoglycans, and meniscal fibrochondrocytes and are the most commonly injured structure of the knee. The tissue is only capable of limited self repair in the case of injury. One exciting new area of research is using metabolomics to study mechanotransduction. This technique quantitatively profiles the processes by which cells respond to mechanical stimuli by biochemical signals that characterize downstream cellular responses. Objective- The objective was to identify candidate mediators of meniscal fibrochondrocyte mechanotransduction in mouse tissues using in vitro organ culture. We aim to uncover metabolomic differences between injured and uninjured tissues and also differences between the tissues in isolation and in combination. Methods- Mouse knee tissue samples were randomly assigned to isolated or combination experimental groups. The structures were cultured for 12 days with half of the menisci being injured. Metabolites were characterized by HPLCMS and untargeted metabolomic analysis to examine changes in global metabolomic profiles. Results- Untargeted metabolomics and cluster analysis revealed changes in 1440 total metabolites, as well as changes in regulation of metabolomic pathways in the response of isolated menisci to injury compared to uninjured isolated menisci. For tissues cultured in combination, similar results were obtained with activation of a larger number of pathways. We discovered a total of 111 metabolic pathways altered by injury. Frequency analysis of individual metabolites in one of the combination samples revealed that the top ten individual metabolites are present in a majority of the upregulated pathways. Conclusions- These data show that metabolomic differences exist between injured and uninjured meniscal fibrochondrocytes, and also metabolomic differences exist when comparing the response of these injured isolated samples to that of injured samples in combination with other knee tissues.
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