Identification of metabolomic signatures in high-fat diet induced acceleration in age-related and surgically induced osteoarthritis in mice

Purpose: We sought to identify the effect of distinct diet regimes towards changes in metabolic profiles and their contributions to the initiation and progression of OA. Methods: 9 weeks old C57BL6 mice were fed high fat diet (HF, 60% fat) and lean diet (LD, 10% fat) for 18 weeks followed by a normal chow diet. Mice were longitudinally evaluated at times 0 (start of diet/baseline), 18 weeks of diet (end of diet), and at 9 months of age. At each time point Dexa (% body fat/ mass index), fasting blood glucose level and body weight were measured. At sacrifice, blood plasma was collected to measure Leptin levels, and metabolite levels by NMR spectroscopy. Knee joints were collected for histopathological analysis by OARSI scoring at 9 months of age. Additional mice on HF and LD diets were subjected to surgical destabilization of the medial meniscus (DMM) to induce experimental OA at the end of 18 week diet regime. Mice were maintained on normal chow until sacrifice at 10 and 20 weeks post surgery where knee joints were collected for histopathological analysis. Results: We determined that HF diet significantly increased fasting blood glucose levels, body weight, BMI and Leptin levels as compared to LD-fed mice. Histopathological analysis using OARSI scoring clearly showed that HF diet-fed mice (in comparison to LD-fed mice) exhibited accelerated spontaneous OA (articular cartilage degeneration and greater chondrocyte loss) at 9 months of age as well as acceleration in the surgically-induced OA at 10 and 20 weeks post surgery. Of the 170 metabolites analyzed in blood plasma at baseline, 18 weeks of diet and at 9 months of age (n=10/group/timepoint), we identified that 3 lysophatidylcholine (lysoPCs) metabolites and 1 phosphotidylcholine metabolite were significantly increased longitudinally in the HF diet-fed mice at 18weeks and at 9 months of age and correlated with the enhanced degree of cartilage degeneration. Our ongoing studies are now evaluating if these lysoPC metabolomic signatures are responsible for initiating and accelerating cartilage degradative process observed in HF diet-fed obese mice. Conclusions: We identified that high fat diet induces and maintains selective metabolic changes and increases OA progression in both spontaneous and surgically-induced OA. We anticipate that these identified metabolomics signatures are involved in OA pathogenesis during obesity.