So much more to mucus: Mammals accommodate a dense community of metabolically active microorganisms in their gut. This is not a passive relationship, and host and microbe have antagonistic as well as mutualistic responses to each other. Using a whole-colon imaging method in mice, Bergstrom et al. looked at the role of colonic mucus in segregating the microbiota from host cells during elimination of feces (see the Perspective by Birchenough and Johansson). Host goblet cells synthesize two forms of mucin that differ in branched chain O-glycosylation and the site of production in the colon. A “thick” mucus in the proximal, ascending colon wraps the microbiota to form fecal pellets. Transit along the distal, descending colon is lubricated by “thin” mucus that transiently links with the thick mucus. Normal mucus encapsulation prevents inflammation and hyperplasia and thus is important for maintenance of a healthy gut. Science , this issue p. 467 ; see also p. 402

Introduction: Obesity is a major risk factor for the development of osteoarthritis in both weight-bearing and nonweight-bearing joints. The mechanisms by which obesity influences the structural or symptomatic features of osteoarthritis are not well understood, but may include systemic inflammation associated with increased adiposity. In this study, we examined biomechanical, neurobehavioral, inflammatory, and osteoarthritic changes in C57BL/6J mice fed a high-fat diet. Methods: Female C57BL/6J mice were fed either a 10% kcal fat or a 45% kcal fat diet from 9 to 54 weeks of age. Longitudinal changes in musculoskeletal function and inflammation were compared with endpoint neurobehavioral and osteoarthritic disease states. Bivariate and multivariate analyses were conducted to determine independent associations with diet, percentage body fat, and knee osteoarthritis severity. We also examined healthy porcine cartilage explants treated with physiologic doses of leptin, alone or in combination with IL-1α and palmitic and oleic fatty acids, to determine the effects of leptin on cartilage extracellular matrix homeostasis. Results: High susceptibility to dietary obesity was associated with increased osteoarthritic changes in the knee and impaired musculoskeletal force generation and motor function compared with controls. A high-fat diet also induced symptomatic characteristics of osteoarthritis, including hyperalgesia and anxiety-like behaviors. Controlling for the effects of diet and percentage body fat with a multivariate model revealed a significant association between knee osteoarthritis severity and serum levels of leptin, adiponectin, and IL-1α. Physiologic doses of leptin, in the presence or absence of IL-1α and fatty acids, did not substantially alter extracellular matrix homeostasis in healthy cartilage explants. Conclusions: These results indicate that diet-induced obesity increases the risk of symptomatic features of osteoarthritis through changes in musculoskeletal function and pain-related behaviors. Furthermore, the independent association of systemic adipokine levels with knee osteoarthritis severity supports a role for adipose-associated inflammation in the molecular pathogenesis of obesity-induced osteoarthritis. Physiologic levels of leptin do not alter extracellular matrix homeostasis in healthy cartilage, suggesting that leptin may be a secondary mediator of osteoarthritis pathogenesis.

Pathobiology of obesity and osteoarthritis: integrating biomechanics and inflammation

Objective: To quantify functional age‐related changes in the cartilage antioxidant network in order to discover novel mediators of cartilage oxidative stress and osteoarthritis (OA) pathophysiology.Methods: We evaluated histopathologic changes of knee OA in 10‐, 20‐, and 30‐month‐old male F344BN rats and analyzed cartilage oxidation according to the ratio of reduced to oxidized glutathione. Antioxidant gene expression and protein abundance were analyzed by quantitative reverse transcription–polymerase chain reaction and selected reaction–monitoring mass spectrometry, respectively. Superoxide dismutase 2 (SOD2) activity and acetylation were analyzed by colorimetric enzyme assays and Western blotting, respectively. We examined human OA cartilage to evaluate the clinical relevance of SOD2 acetylation, and we tested age‐related changes in the mitochondrial deacetylase sirtuin 3 (SIRT‐3) in rats and mice.Results: Cartilage oxidation and OA severity in F344BN rats increased with age and were associated with an increase in SOD2 expression and protein abundance. However, SOD2‐specific activity decreased with age due to elevated posttranslational lysine acetylation. Consistent with these findings, SIRT‐3 levels decreased substantially with age, and treatment with SIRT‐3 increased SOD2 activity in an age‐dependent manner. SOD2 was also acetylated in human OA cartilage, and activity was increased with SIRT‐3 treatment. Moreover, in C57BL/6J mice, cartilage SIRT‐3 expression decreased with age, and whole‐body deletion of SIRT‐3 accelerated the development of knee OA.Conclusion: Our results show that SIRT‐3 mediates age‐related changes in cartilage redox regulation and protects against early‐stage OA. These findings suggest that mitochondrial acetylation promotes OA and that restoration of SIRT‐3 in aging cartilage may improve cartilage resistance to oxidative stress by rescuing acetylation‐dependent inhibition of SOD2 activity.