EFFECTS OF n-3 FATTY ACIDS AND EXERCISE ON OSTEOPOROSIS

绝经后的女性骨质疏松症发病率急剧上升。其原因是由于炎症性骨吸收细胞因子增加而导致破骨细胞增加和成骨细胞活化减少。在今天的美国，有800万女性患有骨质疏松症，1500万女性患有骨质疏松症，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，因此迫切需要替代安全的治疗骨质流失的方法。尽管多种饮食因素与骨质流失有关，但在去卵巢（OVX）动物模型中，n-6（植物）和n-3（鱼）油摄入的作用尚未得到充分研究。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，久坐和在跑步机上运动的n-3脂肪酸喂养的OVX小鼠，DEXA测量的骨质流失明显减少。与饲喂n-3脂肪酸的OVX小鼠相比，玉米油喂养的OVX小鼠骨密度（BMD）下降与T细胞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，这是由于膜脂肪酸的改变导致IL- 1 - β -IL-6、TNFalpha水平和RANKL表达的降低。我们现在提议通过比较sham和OVX对中年（12个月）骨质疏松易感C57BL/6J小鼠的影响来验证这一假设，这些小鼠分别饲喂n-6和n-3饮食，并在有和没有运动的情况下。我们将进行以下研究：1)通过饲喂玉米油饲粮和添加18%二十碳五烯酸（EPA）和12%二十二碳六烯酸（DHA）的除臭鱼油饲粮，测量骨密度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式运动对12月龄OVX小鼠骨密度的联合影响。3)测定n-3和n-6脂肪酸在体外培养时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。综上所述，这些研究将探讨OVX小鼠衰老过程中骨质流失的饮食和分子机制，以及通过低成本的n-3脂质补充和适度运动作为替代HRT的方法来减少骨质流失。

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.