EFFECTS OF n-3 FATTY ACIDS AND EXERCISE ON OSTEOPOROSIS

绝经后的妇女骨质疏松症的发病率急剧上升。其原因与破骨细胞增加和成骨细胞活化减少有关，这是由于炎性骨再吸收细胞因子增加所致。在今天的美国，800万妇女患有骨质疏松症，1500万妇女骨质减少，使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，因此迫切需要替代的安全治疗方法来防止骨丢失。虽然各种饮食因素与骨丢失有关，但在卵巢切除（OVX）动物模型中尚未充分研究n-6（植物）和n-3（鱼油）摄入量的作用。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，久坐和跑步机运动的n-3脂肪酸喂养的OVX小鼠的DEXA测量的骨丢失显著较少。与喂食n-3脂肪酸的OVX小鼠相比，喂食玉米油的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OVX组在补充n-3脂肪酸时，由于膜脂肪酸的改变导致IL-1 β-IL-6和TNF α水平以及RANKL表达降低，破骨细胞活化较少。我们现在建议通过比较假手术和OVX在中年（12个月）糖尿病易感C57 BL/6 J小鼠中的作用来验证这一假设，这些小鼠喂食n-6和n-3饮食，并进行运动和不进行运动。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）的精制鱼油的饮食，测量骨密度和骨组织形态计量学的变化。2)确定n-3脂肪酸与跑步机或自行车运动对12月龄OVX小鼠BMD的联合作用。3)在体外用n-3和n-6脂肪酸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-κ B表达的变化。总之，拟议的研究将调查OVX小鼠衰老过程中骨丢失的饮食和分子机制，以及通过低成本的n-3脂质补充剂和适度运动作为HRT的替代品来减轻骨丢失。

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.