OSTEOBLAST COMMITMENT AND DIFFERENTIATION BY ANGELS

天使对成骨细胞的承诺和差异化

• 批准号: 7327537
• 负责人: STAVROULA KOUSTENI
• 金额: $ 26.93万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7327537
• 关键词: 4-estren-3,17-diol; 4-estren-3alpha,17beta-diol; Adult; Affect; Anabolism; Androgen Receptor; Androgens; Apoptosis; Bone Density; Bone Marrow; Cell model; Cells; Chemosensitization; Class; Collaborations; Commit; Complementary DNA; Embryo; Equilibrium; Estradiol; Estrogen Receptor alpha; Estrogens; Event; Female; Fibroblasts; Genetic Transcription; Glycol; Gonadal Steroid Hormones; Growth Factor; Hindlimb; Human; In Vitro; JNK-activating protein kinase; JUN gene; Laboratories; Lead; Ligands; MAPK8 gene; Mechanics; Mediating; Mesenchymal; Mesenchymal Stem Cells; Metabolic Bone Diseases; Methodology; Modeling; Molecular; Mus; Organ; Osteoblasts; Osteocalcin; Osteoclasts; Osteoporosis; Phosphotransferases; Proteins; Research Personnel; Rodent; Role; Seminal; Serum; Signal Pathway; Signal Transduction; Skeletal system; Skeleton; Small Interfering RNA; Specificity; Stanolone; Technology; Testing; Tissues; Transfection; Width; Work; bone; bone cell; bone morphogenetic protein 2; cytokine; frizzled related protein-1; in vivo; male; member; novel; progenitor; programs; protective effect; receptor; reproductive; reproductive function; transcription factor

DESCRIPTION (provided by applicant): 4-Estren-3alpha,17beta-diol (estren), a synthetic ligand of the estrogen (ER) or androgen (AR) receptor represents a novel class of activators of nongenotropic estrogen-like signaling (ANGELS), compounds that faithfully reproduce the nongenotropic actions of estradiol on osteoblast and osteoclast apoptosis in vitro and in vivo but lack the genotropic effects of classical estrogen. Estren has been shown to have distinct biologic effects compared to estradiol. Unlike estradiol, estren has no effect on female or male reproductive organs but increases serum osteocalcin, cortical width, and bone mineral density of ovariectomized females above the level of the estrogen-replete controls. In view of estren's distinct skeletal profile, versus classical estrogen or other anti-remodeling agents, the postulate that the superior effects of estren must result not only from its favorable effect on bone cell apoptosis, but also from additional mechanisms, will be tested. In studies leading directly to this application, the hypothesis that, unlike estradiol, estren may promote the commitment and/or differentiation of osteoblast progenitors, was explored. Estren induced lineage commitment and differentiation toward osteoblasts via ER-/AR-dependent, kinase-mediated potentiation of BMP-2 and Wnt signaling. Estradiol and DHT are three to four orders of magnitude less potent than estren in these effects. Unlike purported pro-differentiating effects of estradiol, which could be only shown in cells in which the expression of ERalpha was artificially increased by transfection of an ERalpha cDNA, the pro-differentiating effects of estren are demonstrable in bone cells, which express low levels of endogenous ER and AR. Thus, the molecular mechanism of the induction of osteoblast lineage commitment and differentiation by estren will be elucidated by (1) determining the specificity of the ligand/receptor interaction and (2) the involvement of BMP and Wnt signaling in these effects in murine and human osteoblast progenitors and in bone in vivo. A mechanistic explanation will also be sought for why sex steroids, although capable of nongenotropic signaling, differ from estren in their ability to induce lineage commitment and promote osteoblast differentiation, by (3) searching for genotropic counter-regulatory actions on cytokines, kinases, and the BMP and Wnt and signaling pathways. Results of these studies could provide essential understanding for mechanisms to control bone anabolism.

描述（由申请人提供）：4-雌二醇-3 α，17 - β -二醇（雌二醇），一种雌激素（ER）或雄激素（AR）受体的合成配体，代表了一类新型的非基因嗜性雌激素样信号（ANGELS）激活剂，这些化合物在体外和体内都能真实地再现雌二醇对成骨细胞和破骨细胞凋亡的非基因嗜性作用，但缺乏经典雌激素的基因嗜性作用。研究表明，与雌二醇相比，雌二醇具有明显的生物效应。与雌二醇不同，雌二醇对女性或男性生殖器官没有影响，但在卵巢切除的女性中，雌二醇增加血清骨钙素、皮质宽度和骨密度，高于雌激素充满对照组的水平。鉴于雌激素与传统雌激素或其他抗重塑药物相比具有不同的骨骼特征，雌激素的优越作用不仅源于其对骨细胞凋亡的有利作用，还源于其他机制的假设将被验证。在直接导致这一应用的研究中，研究人员探索了一种假设，即与雌二醇不同，雌激素可能促进成骨细胞祖细胞的承诺和/或分化。Estren通过ER-/ ar依赖性、激酶介导的BMP-2和Wnt信号增强诱导成骨细胞的谱系承诺和分化。雌二醇和二氢睾酮在这些作用上比雌二醇弱三到四个数量级。与所谓的雌二醇的促分化作用不同，雌二醇只能在通过转染erα cDNA人工增加erα表达的细胞中表现出促分化作用，而雌激素的促分化作用在表达低水平内源性ER和AR的骨细胞中也能被证明。通过(1)确定配体/受体相互作用的特异性和(2)BMP和Wnt信号在小鼠和人成骨细胞祖细胞以及体内骨中的作用中的参与，将阐明雌激素诱导成骨细胞谱系承诺和分化的分子机制。通过(3)寻找对细胞因子、激酶、BMP和Wnt以及信号通路的基因致异反调节作用，我们还将寻求一个机制上的解释，来解释为什么性类固醇虽然具有非基因致异的信号传导能力，但在诱导谱系承诺和促进成骨细胞分化方面与雌激素不同。这些研究结果为了解骨合成代谢的调控机制提供了重要依据。