|
1000
|
Abstract/Summary
|
-
<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Background</jats:title>
<jats:p>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.</jats:p>
</jats:sec><jats:sec>
<jats:title>Methods</jats:title>
<jats:p>Male and female C57BL/6J mice were fed Chow or HFD from 6 to 26 weeks of age (<jats:italic>n</jats:italic> = 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.</jats:p>
</jats:sec><jats:sec>
<jats:title>Results</jats:title>
<jats:p>Mice fed HFD weighed 1.76-fold (<jats:italic>p</jats:italic> < 0.0001) and 1.60-fold (<jats:italic>p</jats:italic> < 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 (<jats:italic>p</jats:italic> < 0.024) and synovial hyperplasia (<jats:italic>p</jats:italic> < 0.038) versus Chow in both sexes. Cartilage pathology was greater in male versus female mice (<jats:italic>p</jats:italic> = 0.048), and only male mice developed osteophytes with HFD (<jats:italic>p</jats:italic> = 0.044). Both sexes exhibited metabolic inflexibility on HFD, but only male mice developed glucose intolerance (<jats:italic>p</jats:italic> < 0.0001), fatty liver (<jats:italic>p</jats:italic> < 0.0001), and elevated serum amylase (<jats:italic>p</jats:italic> < 0.0001) with HFD versus Chow. HFD treatment caused sex-dependent differences in gut microbiota beta diversity (<jats:italic>p</jats:italic> = 0.01) and alteration in specific microbiome clades, such as a HFD-dependent reduction in abundance of <jats:italic>Bifidobacterium</jats:italic> 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.</jats:p>
</jats:sec><jats:sec>
<jats:title>Conclusions</jats:title>
<jats:p>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.</jats:p>
</jats:sec>
|
