EFFECTS OF n-3 FATTY ACIDS AND EXERCISE ON OSTEOPOROSIS

n-3 脂肪酸和运动对骨质疏松症的影响

• 批准号: 7004505
• 负责人: GABRIEL J J FERNANDES
• 金额: $ 24.95万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7004505
• 关键词: aging; bone density; bone marrow; cell population study; combination therapy; cytokine; diet therapy; dietary supplements; exercise; female; laboratory mouse; lymphocyte; marine animal oil; mature animal; morphometry; nonhuman therapy evaluation; nuclear factor kappa beta; nutrition related tag; omega 3 fatty acid; osteoclasts; osteogenesis; osteoporosis; osteoprotegerin; ovariectomy; vegetable oils

A dramatic rise in osteoporosis occurs in women after menopause. Its cause is linked to increased osteoclasts and decreased osteoblast activation due to increased inflammatory bone resorbing cytokines. In the USA today, 8 million women have osteoporosis and 15 million have osteopenia, placing them at increased risk for osteoporosis and bone fractures. Since hormone replacement therapy (HRT) causes adverse effects, alternative safe therapies against bone loss are badly needed. Although various dietary factors are associated with the bone loss, the roles of n-6 (plant) and n-3 (fish) oil intake have not been fully studied as yet in an ovariectomized (OVX) animal model. Our recent studies have revealed anti-inflammatory effects of fish oil against osteoporosis in OVX mice. Bone loss measured by DEXA was significantly less in both sedentary and treadmill exercised n-3 fatty acid-fed OVX mice compared to corn oil-fed OVX mice. The decreased bone mineral density (BMD) in corn oil-fed OVX mice is correlated with elevated RANKL expression in T cells when compared to OVX mice fed n-3 fatty acids. We hypothesize that the OVX groups will have less osteoclast activation when supplemented with n-3 fatty acids due to alteration in membrane fatty acids resulting in a decrease in IL- 1Beta-IL-6, and TNFalpha levels and RANKL expression. We now propose to test this hypothesis by comparing the effect of sham and OVX in middle-aged (12mo) osteoporosis-prone C57BL/6J mice fed n-6 and n-3 diets with and without exercise. We will carry out the following: 1) Measure changes in BMD and histomorphometry of bones by feeding a corn oil diet and a diet containing deodorized fish oil with 18% eicosapentaenoic acid (EPA) and 12% docosahexaenoic acid (DHA). 2) Determine the combined effects of n-3 fatty acids with treadmill or voluntary wheel exercise on BMD in 12 month old OVX mice. 3) Measure changes in bone marrow and lymphocyte subsets, proinflammatory cytokines, serum leptin and IGF-1 levels, and RANK, RANKL and NF-KappaB expression in vitro with n-3 and n-6 fatty acids. In summary, the proposed studies will investigate the dietary and molecular mechanisms of bone loss during aging in OVX mice and its attenuation by low-cost n-3 lipid supplements with moderate exercise as alternatives to HRT.

绝经后女性的骨质疏松症急剧增加。其原因与破骨细胞增加和炎症性骨吸收细胞因子增加导致成骨细胞活化减少有关。如今，美国有 800 万女性患有骨质疏松症，1500 万女性患有骨质减少症，这使得她们患骨质疏松症和骨折的风险增加。由于激素替代疗法（HRT）会引起不良反应，因此迫切需要针对骨质流失的替代安全疗法。尽管多种饮食因素与骨质流失有关，但 n-6（植物）和 n-3（鱼）油摄入量的作用尚未在卵巢切除 (OVX) 动物模型中得到充分研究。我们最近的研究揭示了鱼油对 OVX 小鼠骨质疏松症的抗炎作用。与玉米油喂养的 OVX 小鼠相比，久坐和跑步机锻炼的 n-3 脂肪酸喂养的 OVX 小鼠通过 DEXA 测量的骨质流失显着减少。与饲喂 n-3 脂肪酸的 OVX 小鼠相比，饲喂玉米油的 OVX 小鼠骨密度 (BMD) 降低与 T 细胞中 RANKL 表达升高相关。我们假设，当补充 n-3 脂肪酸时，OVX 组的破骨细胞活化会减少，因为膜脂肪酸的改变导致 IL-1Beta-IL-6 和 TNFα 水平以及 RANKL 表达降低。我们现在建议通过比较假手术和 OVX 对饲喂 n-6 和 n-3 饮食（有或没有运动）的中年（12 个月）骨质疏松倾向 C57BL/6J 小鼠的影响来检验这一假设。我们将进行以下工作： 1) 通过饲喂玉米油饮食和含有 18% 二十碳五烯酸 (EPA) 和 12% 二十二碳六烯酸 (DHA) 的脱臭鱼油饮食，测量 BMD 和骨骼组织形态学的变化。 2) 确定 n-3 脂肪酸与跑步机或自愿轮运动对 12 个月大 OVX 小鼠 BMD 的综合影响。 3) 用n-3和n-6脂肪酸体外测量骨髓和淋巴细胞亚群、促炎细胞因子、血清瘦素和IGF-1水平以及RANK、RANKL和NF-KappaB表达的变化。总之，拟议的研究将调查 OVX 小鼠衰老过程中骨质流失的饮食和分子机制，以及通过低成本 n-3 脂质补充剂和适度运动作为 HRT 替代品来减轻骨质流失。