Flavonoid Compounds for the Prevention of Osteoporosis

描述（由申请人提供）：估计美国约有1000万人患有骨质疏松症，这种疾病每年导致超过150万例骨折。现在已知，骨髓中脂肪细胞（脂肪细胞）的积累是导致年龄相关性骨质流失的主要因素。骨质疏松症女性的骨髓脂肪细胞数量高于骨健康女性，男性和女性骨组织活检中骨形成率与脂肪细胞数量呈负相关。我们的目标是鉴定天然来源的类黄酮化合物，其抑制骨髓脂肪生成并增加骨中成骨因子的表达，作为预防和治疗骨质疏松症的新策略。我们将筛选大量的黄酮类化合物，以确定这些化合物具有有效的成骨和抗脂肪形成活性，使用以下具体目标：具体目标1将确定类黄酮化合物，抑制小鼠前脂肪细胞（3 T3-L1）细胞系中的脂肪形成。具体目标2将鉴定增加鼠前脂肪细胞（3 T3-L1）细胞系和前成骨细胞鼠细胞系（MC 3 T3-E1）中成骨因子表达的类黄酮化合物。在具体目标3中，我们将使用人骨髓抽吸物的离体培养物验证在鼠细胞系筛选中鉴定的类黄酮化合物的成骨和抗脂肪形成潜力。该研究的第二阶段将涉及在动物模型中测试这些化合物的体内功效，确定化合物之间的潜在协同作用，并验证将这些化合物递送和释放到骨髓微环境中的新方法。

DESCRIPTION (provided by applicant): Approximately 10 million people in the U.S. are estimated to have osteoporosis, a disease that results in over 1.5 million bone fractures a year. It is now known that the accumulation of fat cells (adipocytes) in bone marrow is a major factor contributing to age-related bone loss. Women with osteoporosis have higher numbers of marrow adipocytes than those women with healthy bone, and bone formation rate is inversely correlated with adipocyte number in bone tissue biopsies from both men and women. Our goal is to identify flavonoid compounds from natural sources that inhibit bone marrow adipogenesis and increase the expression of osteogenic factors in bone as a novel strategy for osteoporosis prevention and treatment. We will screen a large number of flavonoids to identify those compounds with potent osteogenic and anti-adipogenic activity using the following specific aims: Specific aim 1 will identify flavonoid compounds that inhibit adipogenesis in a murine preadipocyte (3T3-L1) cell line. Specific aim 2 will identify flavonoid compounds that increase the expression of osteogenic factors in a murine pre-adipocyte (3T3-L1) cell line and a pre-osteoblast murine cell line (MC3T3-E1). In specific aim 3 we will validate the osteogenic and anti-adipogenic potential of the flavonoid compounds identified in the murine cell line screens using ex vivo cultures of human bone marrow aspirates. Phase II of this research will involve testing the efficacy of these compounds in vivo in an animal model, identifying potential synergies between compounds, and validating a novel method of delivering and releasing these compounds into the bone marrow microenvironment.