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• W3200710429 abstract "Osteoarthritis (OA) is the most disabling diseasesglobally, and obesity is a major risk factor for its development,with 66% of individuals with OA being either overweight or obese.Despite this comorbid association, the mechanisms linking obesityto the development of OA have not been fully elucidated. Dogmapurports that increased biomechanical loading in obesity is themain driver of the increased prevalence and acceleration of OA.However, recent studies, from our lab and others, have discoveredthat synovial inflammation and altered insulin signaling isassociated the accelerated progression of OA in obese mice andhumans. These findings led us to hypothesize that while increasedjoint loading may be a factor, obesity-induced pathobiologicalchange in the synovium is the seminal driver of accelerated OAdegeneration of joints. To test this hypothesis, we performed atranscriptomic analysis of synovial tissue from lean and obese miceat a time point prior to development of fulminant jointdegeneration. Significant pro-inflammatory changes were observed inthe obese synovium pre-degeneration, suggesting these changes maybe critical in disease pathogenesis. Pathway analysis of RNAseqresults revealed significant induction of numerous inflammatorypathways including activation of NF-kB, stimulation of macrophagesand B Cells, and altered type 2 diabetes signaling associated withreduced insulin signaling. The macrophage and insulin findingsalign with detection of increased macrophage infiltration intomouse and human synovium, and the ability of insulin to protecthuman synoviocytes from catabolic changes induced by TNF and otherinflammatory cytokines. Since it is established that insulinsignaling is anti-inflammatory in various tissues, we furtherhypothesized that insulin plays an anti-inflammatory role in thesynovial joint, and loss of signaling will lead to the spontaneousonset of OA. To test this hypothesis in vivo, we developed agenetic mouse model of synovial insulin resistance using theCre-Lox system to knockout the insulin receptor (IR) insynoviocytes and superficial zone chondrocytes. IR knockout micedid not spontaneously develop OA, nor did they exhibit exacerbateddisease following injury compared to control mice, indicatingsynovial insulin resistance alone is not sufficient to induce OA,and likely requires the contributing effects of obesity inducedsystemic inflammation as well. Finally, it is now established thatthe influence of obesity on type 2 diabetes and systemicinflammation is directly downstream of an obesity-related dysbiosisof the gut microbiome that is correctable via dietarysupplementation with various indigestible prebiotic fibers. Basedon this we finally hypothesized that i) obesity-induced dysbiosisof the gut microbiome is associated with increased inflammationsystemically and in the synovial joint, and ii) correction of thisdysbiosis with a prebiotic fiber will mitigate acceleration of OAjoint degeneration in obesity. Analysis of the gut microbiome ofobese mice…" @default.
• W3200710429 created "2021-09-27" @default.
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• W3200710429 date "2019-01-01" @default.
• W3200710429 modified "2023-09-23" @default.
• W3200710429 title "The Pathobiology of Osteoarthritis in Obesity: The Roleof Synovial Inflammation, Joint Insulin Resistance, and Dysbiosisof the Gut Microbiome" @default.
• W3200710429 hasPublicationYear "2019" @default.
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