Background: Women have a higher risk of developing osteoarthritis (OA) than men, including with obesity. To better understand this disparity, we investigated sex differences in metabolic and inflammatory factors associated with OA using a diet-induced mouse model of obesity. We hypothesized that 20 weeks of high-fat diet (HFD) would induce sexually dimorphic changes in both systemic and local risk factors of knee OA.
Methods: Male and female C57BL/6J mice were fed Chow or HFD from 6 to 26 weeks of age (n = 12 per diet and sex). We performed broad metabolic phenotyping, 16 S gut microbiome analysis, targeted gene expression analysis of synovium-infrapatellar fat tissue, targeted gene expression and proteomic analysis of articular cartilage, chondrocyte metabolic profiling, and OA histopathology. Two-way ANOVA statistics were utilized to determine the contribution of sex and diet and their interaction on outcomes.
Results: Mice fed HFD weighed 1.76-fold (p < 0.0001) and 1.60-fold (p < 0.0001) more than male and female Chow cohorts, respectively, with both sexes reaching similar body fat levels (male: 43.9 ± 2.2%; female: 44.1 ± 3.8%). HFD caused greater cartilage pathology (p < 0.024) and synovial hyperplasia (p < 0.038) versus Chow in both sexes. Cartilage pathology was greater in male versus female mice (p = 0.048), and only male mice developed osteophytes with HFD (p = 0.044). Both sexes exhibited metabolic inflexibility on HFD, but only male mice developed glucose intolerance (p < 0.0001), fatty liver (p < 0.0001), and elevated serum amylase (p < 0.0001) with HFD versus Chow. HFD treatment caused sex-dependent differences in gut microbiota beta diversity (p = 0.01) and alteration in specific microbiome clades, such as a HFD-dependent reduction in abundance of Bifidobacterium only in male mice. In knee synovium and infrapatellar fat tissue, HFD upregulated the expression of pro-inflammatory and pro-fibrotic genes predominantly in female mice. In cartilage, lipid metabolism proteins were more abundant with HFD in male mice, whereas proteins involved in glycolysis/gluconeogenesis and biosynthesis of amino acids were greater in cartilage of female mice. Sex-dependent metabolic differences were observed in cartilage from young, healthy mice prior to pubertal maturation, but not in primary juvenile chondrocytes studied in vitro.
Conclusions: HFD induced numerous sex differences in metabolic and inflammatory outcomes, especially in joint tissues, suggesting that sex-specific cellular processes are involved during development of early-stage OA with obesity.
Osteoarthritis is a painful and physically disabling synovial joint disease involving progressive degradation of articular cartilage, abnormal bone growth below and adjacent to the cartilage, and variable degrees of inflammation and fibrosis in joint connective tissues. Obesity increases the risk of osteoarthritis due to altered joint loading, increased inflammation, and associated metabolic disorders. Women are more likely to develop osteoarthritis than men, including in the context of obesity. However, the sex-specific factors that increase the risk of osteoarthritis in women are not well understood. We used a well-established mouse model of high-fat diet-induced obesity to investigate sex differences in metabolic and inflammatory risk factors associated with knee osteoarthritis. High-fat diet feeding caused cartilage damage and synovial thickening in both male and female mice, while only male mice developing altered bone growth adjacent to cartilage. Although high-fat diet feeding increased body fat to the same level in both sexes, only male mice developed insulin resistance and fatty livers. Conversely, in knee joint connective tissue, high-fat diet feeding increased the expression of genes that cause inflammation and fibrosis predominately in female mice. Additional sex differences were observed in the cartilage, with high fat diet increasing proteins involved with fat metabolism in male mice, whereas proteins important for carbohydrate and protein metabolism were more abundant in female mice. The numerous metabolic and inflammatory differences observed between male and female mice suggest that sex-specific cellular processes are involved in the development of early-stage osteoarthritis associated with obesity.
Keywords: Cartilage; Gut microbiome; High fat diet; Inflammation; Infra-patellar fat pad; Metabolic syndrome; Obesity; Osteoarthritis; Sex differences.
© 2024. The Author(s).