EFFECTS OF n-3 FATTY ACIDS AND EXERCISE ON OSTEOPOROSIS

绝经后女性患骨质疏松症的几率会急剧上升。其原因是由于炎症性骨吸收细胞因子的增加而导致破骨细胞增多和成骨细胞活性降低。在今天的美国，有800万女性患有骨质疏松症，1500万女性患有骨量减少，这使她们面临着更高的骨质疏松和骨折风险。由于激素替代疗法(HRT)会产生不良反应，因此迫切需要针对骨丢失的安全替代疗法。尽管各种饮食因素与骨质丢失有关，但在去卵巢(OVX)动物模型中，n-6(植物油)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去卵巢小鼠骨质疏松症的抗炎作用。与玉米油喂养的OVX小鼠相比，DEXA测量的骨丢失在久坐和跑步机锻炼的n-3脂肪酸喂养的OVX小鼠中显著减少。与饲喂n-3脂肪酸的去势小鼠相比，喂食玉米油的去势小鼠骨密度降低与T细胞RANKL表达增加有关。我们推测，当补充n-3脂肪酸时，OVX组的破骨细胞活性将会降低，这是由于膜脂肪酸的改变导致IL-1β-IL-6、TNFpha水平和RANKL表达的下降。我们现在建议通过比较Sham和OVX在中年(12mo)易患骨质疏松症的C57BL/6J小鼠中的效果来验证这一假设，这些小鼠在运动和不运动的情况下分别食用n-6和n-3饮食。我们将进行以下工作：1)通过饲喂玉米油和含有18%二十碳五烯酸(EPA)和12%二十二碳六烯酸(DHA)的脱臭鱼油的饲料，测量骨密度和骨组织形态计量学的变化。2)测定n-3脂肪酸联合跑步机运动和车轮运动对12月龄OVX小鼠骨密度的影响。3)用n-3和n-6脂肪酸测定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RANKL和NF-kappaB在体外的表达。综上所述，拟议的研究将探讨OVX小鼠衰老过程中骨丢失的饮食和分子机制，以及作为HRT替代品的低成本n-3脂肪补充剂结合适度运动对骨丢失的缓解作用。

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.