Obesity is a risk factor for osteoarthritis (OA), the greatest cause of disability in the US. The impact of obesity on OA is driven by systemic inflammation, and increased systemic inflammation is now understood to be caused by gut microbiome dysbiosis. Oligofructose, a nondigestible prebiotic fiber, can restore a lean gut microbial community profile in the context of obesity, suggesting a potentially novel approach to treat the OA of obesity. Here, we report that - compared with the lean murine gut - obesity is associated with loss of beneficial Bifidobacteria, while key proinflammatory species gain in abundance. A downstream systemic inflammatory signature culminates with macrophage migration to the synovium and accelerated knee OA. Oligofructose supplementation restores the lean gut microbiome in obese mice, in part, by supporting key commensal microflora, particularly Bifidobacterium pseudolongum. This is associated with reduced inflammation in the colon, circulation, and knee and protection from OA. This observation of a gut microbiome-OA connection sets the stage for discovery of potentially new OA therapeutics involving strategic manipulation of specific microbial species inhabiting the intestinal space.

Purpose of review Osteoarthritis is a debilitating disease leading to joint degeneration, inflammation, pain, and disability. Despite efforts to develop a disease modifying treatment, the only accepted and available clinical approaches involve palliation. Although many factors contribute to the development of osteoarthritis, the gut microbiome has recently emerged as an important pathogenic factor in osteoarthritis initiation and progression. This review examines the literature to date regarding the link between the gut microbiome and osteoarthritis. Recent findings Studies showing correlations between serum levels of bacterial metabolites and joint degeneration were the first links connecting a dysbiosis of the gut microbiome with osteoarthritis. Further investigations have demonstrated that microbial community shifts induced by antibiotics, a germ-free environment or high-fat are important underlying factors in joint homeostasis and osteoarthritis. It follows that strategies to manipulate the microbiome have demonstrated efficacy in mitigating joint degeneration in osteoarthritis. Moreover, we have observed that dietary supplementation with nutraceuticals that are joint protective may exert their influence via shifts in the gut microbiome. Summary Although role of the microbiome in osteoarthritis is an area of intense study, no clear mechanism of action has been determined. Increased understanding of how the two factors interact may provide mechanistic insight into osteoarthritis and lead to disease modifying treatments.

The aim of this study was to analyze the anti-inflammatory effect of VA692, in comparison with celecoxib. In addition, we would establish if the new compound presents any advantages over other COX-2 inhibitors already available in therapeutic use. By iTRAQ methodology, we quantitatively analyzed the different expressed profiles in T/C-28a2 cell line treated with the studied drugs in presence of IL-1b. Methods: Human T/C-28a2 chondrocytes cell line were generated by Goldring group. Human articular cartilage was obtained from femoral heads of five OA patients. Cells were incubated with VA692 and celecoxib (1, 0.5 and 0.2mM) with interleukin (IL)-1b (5ng/ml) for 48hrs. The expression of inflammatory cytokines and anti-oxidant enzymes was evaluated by quantitative qRT-PCR, prostaglandins (PG)-E 2 release by ELISA. Apoptosis levels and ROS production were evaluated by flow cytometry. Proteins extracted by T/C-28a2 cell line was employed to carry out western blot analysis and the iTRAQ methodology. Statistical analysis was performed by ANOVA and Bonferroni multiple comparison tests. Results: IL-1b-stimulated chondrocytes showed a significant increase (p<0.001) of COX-2, IL-1b, IL-6, IL-8, superoxide dismutase (SOD)-2 and catalase (CAT) gene expression, as well as of PGE 2 levels in OA chondrocyte and in T/C-28a2 cell line. The tested drugs significantly counteracted the effect of IL-1b, with a better modulation by VA692 1mM in T/C-28a2 (p<0.01 for COX-2, IL-1b, IL-8, CAT; p<0.001 for IL-6, SOD-2 and PGE 2). Regarding apoptosis and mitochondrial superoxide anion production, the new drug was able to significantly reduce (p<0.05) their increase induced by IL-1b (p<0.05). Proteomic analysis led to the identification of 797 proteins in T/C-28a2 cell line, 123 of which were significantly modulated by VA692 in presence of IL-1b (p<0.001), while 34 were modulated by IL-1b alone (p<0.05). 21 proteins were commonly modulated by the two groups, indicating that 101 proteins were regulated by VA692 in a specific manner. Among the proteins downregulated by VA692, some with structural function were detected, responsible for cytoskeleton reorganization, as well as chaperones (heat shock proteins) and glycolitic enzymes. Proteins involved in calcium metabolism and in ribosome biogenesis resulted up-regulated instead, as well as SOD-2 as confirmed by western blot analysis. Conclusions: Our data demonstrated the anti-inflammatory effect of VA692, suggesting also its anti-apoptotic and anti-oxidant role. The proteomic analysis demonstrated that VA692 induced not only an antiinflammatory regulation in chondrocytes but, interestingly, seemed to regulate their anabolic response. On the basis of our results, we can hypothesize that VA692 could present any advantages over other COX-2 inhibitors already available for therapeutic use. However, further in vitro and in vivo experiments are necessary to elucidate and confirm the importance of this pharmacological compound before its use in the therapeutic approach of joint diseases.

Purpose: The growing incidence of osteoarthritis (OA) is linked to the expanding epidemic of obesity, with 66% of all OA patients classified as obese. While dogma has implicated joint overloading as causal, our clinical and animal findings suggest that the comorbid association between OA and obesity includes a systemic inflammatory cause-andeffect relationship, the nature of which is not defined. Intriguingly, it has recently been discovered that a key driver of obesity-induced systemic inflammation is an altered gut microbiome, which is characterized by an increase in various proinflammatory microbial species. Dietary supplementation with agents that support expansion of Actinobacteria, including the insoluble and undigestible prebiotic fiber oligofructose, can correct the obese/proinflammatory gut microbiome, suggesting therapeutic potential in the OA of obesity. These findings lead us to hypothesize that prebiotic supplementation of obese mice with oligofructose will correct the obese gut microbiome, mitigate systemic inflammation, and decelerate the progression of OA. Methods: Male C57BL/6 mice were fed a lean or high fat diet (HF) for 12 weeks, at which point they were provided a lean or HF diet Abstracts / Osteoarthritis and Cartilage 25 (2017) S8eS75 S11