The effects of metabolic syndrome, obesity, and the gut microbiome on load-induced osteoarthritis J.D. Guss, S.N. Ziemian, M. Luna, T.N. Sandoval, D.T.

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The effects of metabolic syndrome, obesity, and the gut microbiome on load-induced osteoarthritis J.D. Guss, S.N. Ziemian, M. Luna, T.N. Sandoval, D.T. Holyoak, G.G. Guisado, S. Roubert, R.L. Callahan, I.L. Brito, M.C.H. van der Meulen, S.R. Goldring, C.J. Hernandez Osteoarthritis and Cartilage Volume 27, Issue 1, Pages 129-139 (January 2019) DOI: 10.1016/j.joca.2018.07.020 Copyright © 2018 Osteoarthritis Research Society International Terms and Conditions

Fig. 1 TLR5KO mice displayed hallmarks of metabolic syndrome including increased (A) body mass, (B) epididymal fat pad mass, (C) serum insulin levels, and (D) serum leptin levels compared to WT mice. HFD mice had increased levels of adiposity, insulin, and leptin. Body mass and epididymal fat pad mass are pooled from 22 week and 26 week old animals. Serum is from 26-week old mice. Solid colored lines on dot plots represent the mean value. Groups sharing the same letter are not significantly different from each other (p < 0.05). Osteoarthritis and Cartilage 2019 27, 129-139DOI: (10.1016/j.joca.2018.07.020) Copyright © 2018 Osteoarthritis Research Society International Terms and Conditions

Fig. 2 Twenty-week old male mice were subjected to either 2 or 6 weeks of cyclic mechanical loading to induce OA pathology. (A) After both 2 weeks and 6 weeks of mechanical loading there was an effect of load on OA pathology as measured by OARSI score. No differences the effect of loading were observed among groups at 2 weeks, however, after 6 weeks of loading, HFD mice had elevated loaded limb OARSI scores compared to other groups, and TLR5KOΔMicrobiota mice had lower loaded limb OARSI scores (upper case letters used to denote group differences of loaded limb OARSI scores). Control limb OARSI scores were greater in HFD mice compared to TLR5KOΔMicrobiota mice after 6 weeks of loading (lower case letters used to denote group differences of control limb OARSI scores). (B) Example histology of control and loaded limbs is shown with surface fibrillations and vertical clefts identified. (C) Modified Mankin scores were greater in HFD and TLR5KOΔMicrobiota mice compared to WT. Solid colored bars on plots represent mean. Groups sharing the same letter are not significantly different from each other (p < 0.05). Osteoarthritis and Cartilage 2019 27, 129-139DOI: (10.1016/j.joca.2018.07.020) Copyright © 2018 Osteoarthritis Research Society International Terms and Conditions

Fig. 3 Measures of subchondral and epiphyseal bone after 6 weeks of loading are shown. (A) TLR5KOΔMicrobiota mice showed lower levels of subchondral tissue mineral density (TMD). (B) Control limb subchondral bone TMD was correlated with loaded limb OARSI scores (r = 0.69, 95% confidence interval of correlation coefficient: [0.40, 0.86]). A Pearson's product-moment correlation analysis was used to identify relationships between loaded limb OARSI scores and control limb subchondral bone TMD. (C) TLR5KOΔMicrobiota mice showed lower levels of subchondral bone thickness as compared to other groups. (D) Epiphyseal bone volume fraction was less in HFD mice compared to other groups. Solid colored lines on dot plots represent mean. Groups sharing the same letter are not significantly different from each other (p < 0.05). Osteoarthritis and Cartilage 2019 27, 129-139DOI: (10.1016/j.joca.2018.07.020) Copyright © 2018 Osteoarthritis Research Society International Terms and Conditions

Fig. 4 Serum markers after 6 weeks of loading are shown. Mice fed HFD had elevated (A) serum lipopolysaccharide (LPS). (B) Serum LPS was correlated with loaded limb OARSI scores in untreated animals. Among the WT, HFD, and TLR5KO groups, LPS explained 44% of the variation in OARSI score across groups (R2 = 0.44, P = 0.0003). HFD mice also had elevated serum levels of (C) KC and (D) IL-10. Solid colored lines on dot plots represent mean. Groups sharing the same letter are not significantly different from each other (P < 0.05). Osteoarthritis and Cartilage 2019 27, 129-139DOI: (10.1016/j.joca.2018.07.020) Copyright © 2018 Osteoarthritis Research Society International Terms and Conditions

Fig. 5 The taxonomic profile of the gut microbiota from animals after 6 weeks of loading is shown. (A) There are large differences in the relative abundance of organisms at the phyla level. (B) The relative abundance of Bacteroidetes was greatest in TLR5KO and WT mice. (C) The relative abundance of Firmicutes was greatest in HFD mice and (D) the relative abundance of Proteobacteria was greatest in TLR5KOΔMicrobiota mice. (E) Principal coordinate analysis based on the Bray–Curtis dissimilarity shows that each group forms its own distinct clusters from each other. Bacterial diversity was dramatically reduced in TLR5KOΔMicrobiota mice (F). Solid colored lines on dot plots represent mean. * p < 0.05. Osteoarthritis and Cartilage 2019 27, 129-139DOI: (10.1016/j.joca.2018.07.020) Copyright © 2018 Osteoarthritis Research Society International Terms and Conditions

figs1 Osteoarthritis and Cartilage 2019 27, 129-139DOI: (10.1016/j.joca.2018.07.020) Copyright © 2018 Osteoarthritis Research Society International Terms and Conditions

figs2 Osteoarthritis and Cartilage 2019 27, 129-139DOI: (10.1016/j.joca.2018.07.020) Copyright © 2018 Osteoarthritis Research Society International Terms and Conditions

figs3 Osteoarthritis and Cartilage 2019 27, 129-139DOI: (10.1016/j.joca.2018.07.020) Copyright © 2018 Osteoarthritis Research Society International Terms and Conditions

figs4 Osteoarthritis and Cartilage 2019 27, 129-139DOI: (10.1016/j.joca.2018.07.020) Copyright © 2018 Osteoarthritis Research Society International Terms and Conditions

figs5 Osteoarthritis and Cartilage 2019 27, 129-139DOI: (10.1016/j.joca.2018.07.020) Copyright © 2018 Osteoarthritis Research Society International Terms and Conditions

figs6 Osteoarthritis and Cartilage 2019 27, 129-139DOI: (10.1016/j.joca.2018.07.020) Copyright © 2018 Osteoarthritis Research Society International Terms and Conditions

figs7 Osteoarthritis and Cartilage 2019 27, 129-139DOI: (10.1016/j.joca.2018.07.020) Copyright © 2018 Osteoarthritis Research Society International Terms and Conditions

figs8 Osteoarthritis and Cartilage 2019 27, 129-139DOI: (10.1016/j.joca.2018.07.020) Copyright © 2018 Osteoarthritis Research Society International Terms and Conditions