Transgenic conversion of ω-6 to ω-3 polyunsaturated fatty acids via fat-1 reduces the severity of post-traumatic osteoarthritis
Transgenic conversion of ω-6 to ω-3 polyunsaturated fatty acids via fat-1 reduces the severity of post-traumatic osteoarthritis
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DOI：
10.1186/s13075-020-02170-7
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发表时间：
2020-04-15
影响因子：
4.9
通讯作者：
Guilak, Farshid
中科院分区：
文献类型：
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作者：
Kimmerling, Kelly A.;Oswald, Sara J.;Guilak, Farshid
背景：膳食脂肪酸(FA)的含量已被证明影响肥胖患者创伤后骨关节炎(PTOA)的发生。我们利用转基因的FAT-1小鼠验证了这样的假设，即在相同的饮食条件下，内源性降低omega-6与omega-3 FA的比例可以减轻肥胖雄性和雌性小鼠的代谢性炎症和PTOA的发病。方法雄性和雌性Fat-1和野生型仔鼠分别饲喂对照饲料和富含omega-6 FA的高脂饲料，并进行内侧半月板(DMM)手术失稳以诱导PTOA。通过组织学方法确定骨关节炎的严重程度、滑膜炎症和骨赘形成，同时进行生物标志物和脂类分析以评估血清和关节滑液中脂肪因子、胰岛素、促炎/抗炎细胞因子和FAs的水平。多变量模型被用来阐明饮食、代谢和机械因素与PTOA的关系。结果我们发现，与喂食相同饮食的野生型对照组相比，肥胖-1小鼠血清中omega-3 FAs水平的升高导致了OA和滑膜炎的减少，这一结果与性别和饮食有关，尽管体重相当。FAT-1小鼠表现出血清促炎细胞因子降低和抗炎细胞因子增加的趋势。对预测小鼠骨性关节炎严重程度的变量进行多变量分析，结果是与血清FA水平相关，但与体重无关。结论本研究提供了进一步的证据，即循环FA成分和全身代谢性炎症，而不是体重，可能是肥胖相关骨性关节炎的主要危险因素。我们还证明了omega-3FA去饱和酶在减轻损伤后肥胖患者PTOA方面的潜在遗传学用途。
Background Dietary fatty acid (FA) content has been shown to influence the development of post-traumatic osteoarthritis (PTOA) in obesity. We used the fat-1 transgenic mouse to examine the hypothesis that endogenous reduction of omega-6 to omega-3 FA ratio, under the same dietary conditions, would mitigate metabolic inflammation and the pathogenesis of PTOA in obese male and female mice. Methods Male and female fat-1 and wild-type littermates were fed either a control diet or an omega-6 FA-rich high-fat diet and underwent destabilization of the medial meniscus (DMM) surgery to induce PTOA. OA severity, synovitis, and osteophyte formation were determined histologically, while biomarker and lipidomic analyses were performed to evaluate levels of adipokines, insulin, pro-/anti-inflammatory cytokines, and FAs in serum and joint synovial fluid. Multivariable models were performed to elucidate the associations of dietary, metabolic, and mechanical factors with PTOA. Results We found that elevated serum levels of omega-3 FAs in fat-1 mice as compared to wild-type controls fed the same diet resulted in reduced OA and synovitis in a sex- and diet-dependent manner, despite comparable body weights. The fat-1 mice showed trends toward decreased serum pro-inflammatory cytokines and increased anti-inflammatory cytokines. Multivariable analysis for variables predicting OA severity in mice resulted in correlations with serum FA levels, but not with body weight. Conclusions This study provides further evidence that circulating FA composition and systemic metabolic inflammation, rather than body weight, may be the major risk factor for obesity-associated OA. We also demonstrate the potential genetic use of omega-3 FA desaturase in mitigating PTOA in obese patients following injury.