Food Bioactives and Bone Metabolism

这项研究计划的重点是纠正或减轻在衰老过程中发生的骨转换失调，使用食品和药物的协同作用。我们假设，食物生物活性物质(茶叶中的黄酮类)与药物干预(低剂量雌激素)相结合，可以提供一种安全有效的策略来正常化骨转换。女性习惯性饮茶与较高的骨密度(BMD)密切相关，而男性的相关数据较少。茶叶中的黄酮类化合物可能是介导这些益处的活性成分，并通过多种机制发挥作用，包括雌激素样作用、抗氧化活性和抗炎活性。我们有很有希望的数据表明，木犀草素和冬凌草素，这两种绿茶、红茶和绿茶所特有的黄酮类化合物，可以刺激成骨细胞的活动。这些数据为拟议的研究提供了强有力的理论基础，该研究旨在调查TEA在年龄介导性类固醇下降的啮齿动物模型中促进骨转换的能力(去卵巢(OVX)和去(Orch)大鼠)。*总体目标是阐明食物生物活性物质(即绿茶、红茶和红茶中的黄酮类化合物)单独或与低剂量雌激素联合作用调节骨细胞代谢的机制。总体假设是，与单独提供黄酮类或低剂量雌激素相比，从茶叶中提取的类黄酮与低剂量雌激素一起提供将在更大程度上刺激成骨细胞的活动，并下调破骨细胞的活动。*科学方法包括使用成熟的OVX或Orch大鼠模型来模拟正常衰老过程中骨细胞代谢的变化，这些变化会导致氧化应激水平升高和导致骨细胞代谢(形成、吸收)的低度炎症。通过对OVX和Orch大鼠骨组织的分析，可以通过测定成骨细胞活动的五个主要方面的关键介质的水平和活性来确定单独的饮食策略或低剂量雌激素通过调节氧化应激和低度炎症的机制。这些方面包括对I.细胞数量的调节；ii.矩阵制作；3.生长因子的表达和反应性；调节骨吸收的因素；以及V.受体的表达和信号转导。为了了解这些机制如何与整个骨骼相关，在整个研究过程中，将在同一只大鼠身上测量骨密度、骨强度和三维骨骼结构等骨功能指标。脂肪和瘦体重也将被测量，因为它们可能会通过干预改变并调节骨骼结果。*预期意义：这项研究将阐明茶叶中的黄酮类物质可能有助于调节骨骼细胞代谢的机制，以及增强或减弱雌激素治疗缓解骨骼代谢失调的能力。**

This research program has focused on correcting or attenuating the dysregulation of bone turnover that occurs during aging using food-drug synergy. We hypothesize that food bioactives (flavonoids from tea) in combination with drug interventions (low dose estrogen) can provide a safe and effective strategy to normalize bone turnover. Habitual consumption of tea is strongly associated with higher bone mineral density (BMD) in women with less data in men. Flavonoids in tea may be the active component mediating these benefits and through multiple mechanisms, including estrogen-like effects, antioxidant activity and anti-inflammatory activity. We have promising data that luteolin and orientin, flavonoids unique to rooibos tea - and that providing green, black and rooibos tea - stimulate osteoblast activity. These data provide a strong rationale for the proposed studies investigating tea and its ability to promote regulation of bone turnover in rodent models of age-mediated declines in sex steroids (ovariectomized (Ovx) and orchidectomized (Orch) rats). ******The overall objective is to elucidate the mechanisms by which food bioactives (i.e. flavonoids from green, black and rooibos tea) alone or in combination with low dose estrogen modulate bone cell metabolism. The overall hypothesis is that providing flavonoids from tea with low dose estrogen will stimulate osteoblast activity and downregulate osteoclastic activity to a greater extent than flavonoids or low dose estrogen alone. ******The scientific approach involves using the well-established Ovx or Orch rat model to simulate changes in bone cell metabolism that occur during normal aging and result in elevated levels of oxidative stress and low-grade inflammation that uncouples bone cell metabolism (formation,resorption). Analysis of bone tissue from Ovx and Orch rats can determine mechanisms by which dietary strategies alone, or with low dose estrogen, modulate oxidant stress and low-grade inflammation by determining the levels and activity of key mediators of five main aspects of osteoblast activity. These aspects include regulation of i. cell numbers; ii. matrix production; iii. growth factor expression and responsiveness; iv. factors that modulate bone resorption; and v. receptor expression and signal transduction. To understand how these mechanisms relate to whole bone, in vivo functional measures of bone such as BMD, bone strength and 3-dimensional bone structure will be measured in the same rat throughout the study. Fat and lean mass will also be measured as they may be altered by an intervention and modulate bone outcomes.******Expected significance: This research will elucidate the mechanisms by which flavonoids from tea may favourably regulate bone cell metabolism, and also, augment or lessen the ability of estrogen therapy to attenuate dysregulation of bone metabolism.**