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Chondrocyte Metabolic Flexibility and Early‐Stage Osteoarthritis in Mice Fed a High‐Fat Diet
Author(s) -
Donovan Elise,
Hudson Joanna,
Kinter Mike,
Griffin Timothy
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb656
Subject(s) - chondrocyte , osteoarthritis , medicine , endocrinology , cartilage , catabolism , pathogenesis , aggrecan , chemistry , pathology , metabolism , articular cartilage , anatomy , alternative medicine
Obesity is a primary risk factor for osteoarthritis (OA). However, how chondrocyte metabolism changes in response to a high‐fat diet (HFD) and the mechanisms by which obesity initiates and promotes pro‐catabolic changes in chondrocytes that lead to OA are not fully understood. The objective of this study was to better understand the initiating cellular factors associated with OA pathogenesis in high‐fat diet (HFD)‐induced obese mice by examining changes in the expression of chondrocyte metabolic pathway components. Methods Male C57BL/6J mice (n = 10–12 per diet per time point) were fed either a HFD (60% kcal fat) or a control diet (Ctr; 10% kcal fat) beginning at 6 weeks of age. Knee OA histopathology was examined using a modified Mankin OA scoring system following 20, 32, and 46 weeks of HFD feeding. In the 32‐week cohort, chondrocyte intracellular lipid accumulation was measured by oil red O staining. In an additional cohort of animals at 20 weeks (n = 3–5), mRNA and protein were isolated from knee articular cartilage to examine chondrocyte transcriptional and protein expression changes. Results HFD for 20 weeks increased osteophyte formation (p = 0.03) and tidemark duplication (p = 0.03) but did not increase the modified Mankin OA score, which was only significantly increased after 46 weeks on the HFD (p = 0.02). Because early osteoarthritic changes were observed by 20 weeks of HFD feeding, we examined cartilage transcriptional changes at this time point. None of the extracellular matrix genes (Aggrecan, Col10, Col2a) or matrix degrading proteases (Mmp9, Mmp13, Adamts5) were differentially expressed in HFD animals compared to Ctr at this time point, consistent with the histology. Cpt1a gene (1.4 fold increase, p = 0.03) and protein (1.87 fold increase, p = 0.04) expression were increased in the HFD group, suggesting increased transport of fatty acids into the mitochondria for oxidation. Of the 16 glycolysis related proteins examined, 62% were decreased in HFD animals (outside the reference gene CV range of 0.94 – 1.06), and of the 15 β‐oxidation proteins examined, 63% were increased in HFD animals. After 32 weeks of HFD, the percentage of chondrocytes containing lipid droplets remained unchanged. Conclusion HFD did not alter lipid droplet accumulation but did increase Cpt1a gene and protein expression, and there was a general trend for an increase in β‐oxidation proteins and a decrease in glucose metabolism proteins. These data suggest that in response to HFD chondrocyte lipid uptake and flux are increased while glucose utilization is likely decreased; these metabolic changes preceded HFD induced cartilage degradation. Support or Funding Information Supported by the NIH and Arthritis Foundation.