Griffin Timothy M, Lopes Erika Barboza Prado, Cortassa Dominic, Batushansky Albert, Jeffries Matlock A, Makosa Dawid, Jopkiewicz Anita, Mehta-D'souza Padmaja, Komaravolu Ravi K, Kinter Michael T
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.
Veterans Affairs Medical Center, Oklahoma City, OK, 73104, USA.
Biol Sex Differ. 2024 Dec 5;15(1):103. doi: 10.1186/s13293-024-00680-6.
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.
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.
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.
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.
女性患骨关节炎（OA）的风险高于男性，肥胖时亦是如此。为了更好地理解这种差异，我们使用饮食诱导的肥胖小鼠模型，研究了与OA相关的代谢和炎症因子的性别差异。我们假设，20周的高脂饮食（HFD）会在膝关节OA的全身和局部危险因素中诱导出性别二态性变化。
雄性和雌性C57BL/6J小鼠在6至26周龄期间分别喂食普通饲料或高脂饲料（每种饮食和性别n = 12）。我们进行了广泛的代谢表型分析、16S肠道微生物群分析、滑膜 - 髌下脂肪组织的靶向基因表达分析、关节软骨的靶向基因表达和蛋白质组分析、软骨细胞代谢谱分析以及OA组织病理学分析。采用双向方差分析统计来确定性别和饮食及其相互作用对结果的影响。
喂食高脂饮食的小鼠体重分别比雄性和雌性普通饲料组小鼠重1.76倍（p < 0.0001）和1.60倍（p < 0.0001），两性的体脂水平相似（雄性：43.9 ± 2.2%；雌性：44.1 ± 3.8%）。与普通饲料相比，高脂饮食在两性中均导致更大程度的软骨病变（p < 0.024）和滑膜增生（p < 0.038）。雄性小鼠的软骨病变比雌性小鼠更严重（p = 0.048），并且只有雄性小鼠在高脂饮食下出现骨赘（p = 0.044）。两性在高脂饮食下均表现出代谢灵活性受损，但只有雄性小鼠在高脂饮食与普通饲料相比时出现葡萄糖不耐受（p < 0.0001）、脂肪肝（p < 0.0001）和血清淀粉酶升高（p < 0.0001）。高脂饮食处理导致肠道微生物群β多样性存在性别依赖性差异（p = 0.01），并改变了特定的微生物群落，例如仅在雄性小鼠中，高脂饮食导致双歧杆菌丰度降低。在膝关节滑膜和髌下脂肪组织中，高脂饮食主要在雌性小鼠中上调促炎和促纤维化基因的表达。在软骨中，高脂饮食使雄性小鼠的脂质代谢蛋白更丰富，而参与糖酵解/糖异生和氨基酸生物合成的蛋白在雌性小鼠的软骨中含量更高。在青春期前成熟的年轻健康小鼠的软骨中观察到了性别依赖性代谢差异，但在体外研究的原代幼年软骨细胞中未观察到。
高脂饮食在代谢和炎症结果方面诱导了许多性别差异，尤其是在关节组织中，这表明在肥胖相关的早期OA发展过程中涉及性别特异性细胞过程。
