University of Rochester School of Medicine and Dentistry
Abstract
Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pathology and Laboratory Medicine, 2018.Osteoarthritis (OA) is the most disabling diseases globally, 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 obesity to the development of OA have not been fully elucidated. Dogma purports that increased biomechanical loading in obesity is the main driver of the increased
prevalence and acceleration of OA. However, recent studies, from our lab and others, have discovered that synovial inflammation and altered insulin signaling is associated the accelerated progression of OA in obese mice and humans. These findings led us to hypothesize that while increased joint loading may be a factor, obesity-induced pathobiological change in the synovium is the seminal driver of accelerated OA degeneration of joints. To test this hypothesis, we performed a transcriptomic analysis of synovial tissue from lean and obese mice at a time point prior to development of fulminant joint degeneration. Significant pro-inflammatory changes were observed in the obese synovium pre-degeneration, suggesting these changes may be critical in disease pathogenesis. Pathway analysis of RNAseq results revealed significant induction of numerous inflammatory pathways including activation of NF-kB, stimulation of macrophages and B Cells, and altered type 2 diabetes signaling associated with
reduced insulin signaling. The macrophage and insulin findings align with detection of increased macrophage infiltration into mouse and human synovium, and the ability of insulin to protect human synoviocytes from catabolic changes induced by TNF and other inflammatory cytokines. Since it is established that insulin signaling is anti-inflammatory in various tissues, we further hypothesized
that insulin plays an anti-inflammatory role in the synovial joint, and loss of signaling will lead to the spontaneous onset of OA. To test this hypothesis in vivo, we developed a genetic mouse model of synovial insulin resistance using the Cre-Lox system to knockout the insulin receptor (IR) in synoviocytes and superficial zone chondrocytes. IR knockout mice did not spontaneously develop OA, nor did they exhibit exacerbated disease following injury compared to control mice, indicating synovial insulin resistance alone is not sufficient to induce OA, and likely requires the contributing effects of obesity induced systemic inflammation as well. Finally, it is now established that the influence of obesity on type 2 diabetes and systemic inflammation is directly downstream of an obesity-related dysbiosis of the gut microbiome that is correctable via dietary supplementation with various indigestible prebiotic fibers. Based on this we finally hypothesized that i) obesity-induced dysbiosis of the gut microbiome is associated with increased inflammation systemically and in the synovial joint, and ii) correction of this dysbiosis with a prebiotic fiber will mitigate acceleration of OA joint degeneration in obesity. Analysis of the gut microbiome of obese mice revealed an almost complete loss of the anti-inflammatory microbe,
Bifidobacterium pseudolongum. Remarkably, dietary supplementation with the indigestible fiber oligofructose corrected this dysbiosis, leading to a more than a 1,000-fold increase in Bifidobacterium pseudolongum in the obese gut microbiome. Associated with this shift were anti-inflammatory effects in the colon, the systemic circulation, and the synovium and protection from the obesity induced
acceleration of cartilage degeneration. Taken together, findings presented here establish that pathobiological pro-inflammatory changes in the synovium are key precursors driving the accelerated disease progression in the OA of Obesity. Additionally, we implicate a dysbiotic gut microbiome as pathogenic in this context, and demonstrate that prebiotic correction of this dysbiosis is a novel therapeutic strategy for treating the OA of obesity, a disease for which there are no clinically
accepted treatment approaches