OSTEOBLAST COMMITMENT AND DIFFERENTIATION BY ANGELS

天使对成骨细胞的承诺和差异化

基本信息

  • 批准号:
    6861687
  • 负责人:
  • 金额:
    $ 24.99万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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(申请人提供):4-Estren-3α,17β-diol(Estren),雌激素(ER)或雄激素(AR)受体的合成配体代表了一类新的非遗传性雌激素样信号激活剂(Angels),这些化合物忠实地复制了雌二醇在体外和体内对成骨细胞和破骨细胞凋亡的非遗传性作用,但缺乏经典雌激素的遗传学作用。Estren已被证明与雌二醇相比具有明显的生物效应。与雌二醇不同,Estren对女性或男性生殖器官没有影响,但增加了去卵巢女性的血清骨钙素、皮质骨宽度和骨密度,高于雌激素充足对照组的水平。鉴于Estren独特的骨骼特征,与经典的雌激素或其他抗重塑药物相比,Estren的优越效果不仅来自于它对骨细胞凋亡的有利作用,还来自于其他机制,这一假设将得到检验。在直接导致这一应用的研究中,探索了Estren可能促进成骨细胞前体细胞的承诺和/或分化的假设,这与雌二醇不同。Estren通过ER/AR依赖的、激酶介导的BMP-2和Wnt信号的增强,诱导向成骨细胞的谱系承诺和分化。在这些作用上,雌二醇和DHT的效力比Estren小三到四个数量级。雌二醇的促分化作用只能在细胞中通过转导ERpha基因人工增加ERpha的表达,与此不同,Estren的促分化作用在表达低水平内源性ER和AR的骨细胞中可见。因此,Estren诱导成骨细胞向成骨细胞定向分化的分子机制将通过(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、人成骨细胞前体细胞和活体骨骼中的参与。(3)寻找细胞因子、激酶、BMP、Wnt和信号通路上的遗传反向调节作用,从机制上解释为什么性激素虽然具有非遗传性信号转导功能,但在诱导谱系承诺和促进成骨细胞分化的能力上与Estren不同。这些研究的结果可以为控制骨合成代谢的机制提供必要的了解。

项目成果

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会议论文数量(0)
专利数量(0)

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STAVROS C. MANOLAGAS其他文献

STAVROS C. MANOLAGAS的其他文献

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{{ truncateString('STAVROS C. MANOLAGAS', 18)}}的其他基金

Estrogens, androgens, aging, and bone loss in males
男性雌激素、雄激素、衰老和骨质流失
  • 批准号:
    8244288
  • 财政年份:
    2012
  • 资助金额:
    $ 24.99万
  • 项目类别:
Estrogens, androgens, aging, and bone loss in males
男性雌激素、雄激素、衰老和骨质流失
  • 批准号:
    8413601
  • 财政年份:
    2012
  • 资助金额:
    $ 24.99万
  • 项目类别:
Androgens, estrogens, and bone loss in males
男性雄激素、雌激素和骨质流失
  • 批准号:
    10254219
  • 财政年份:
    2012
  • 资助金额:
    $ 24.99万
  • 项目类别:
Estrogens, androgens, aging, and bone loss in males
男性雌激素、雄激素、衰老和骨质流失
  • 批准号:
    8598056
  • 财政年份:
    2012
  • 资助金额:
    $ 24.99万
  • 项目类别:
Androgens, estrogens, and bone loss in males
男性雄激素、雌激素和骨质流失
  • 批准号:
    9240823
  • 财政年份:
    2012
  • 资助金额:
    $ 24.99万
  • 项目类别:
ADMINISTRATIVE CORE
行政核心
  • 批准号:
    7094985
  • 财政年份:
    2006
  • 资助金额:
    $ 24.99万
  • 项目类别:
MOLECULAR MECHANISMS OF THE SKELETAL EFFECTS OF ESTROGEN IN OLD AGE
雌激素对老年骨骼影响的分子机制
  • 批准号:
    7094994
  • 财政年份:
    2006
  • 资助金额:
    $ 24.99万
  • 项目类别:
OSTEOBLAST COMMITMENT AND DIFFERENTIATION BY ANGELS
天使对成骨细胞的承诺和差异化
  • 批准号:
    7012312
  • 财政年份:
    2005
  • 资助金额:
    $ 24.99万
  • 项目类别:
HORMONAL CONTROL OF CYTOKINES IN BONE AND MARROW CELLS
骨细胞和骨髓细胞中细胞因子的激素控制
  • 批准号:
    6316954
  • 财政年份:
    2000
  • 资助金额:
    $ 24.99万
  • 项目类别:
HORMONAL CONTROL OF CYTOKINES IN BONE AND MARROW CELLS
骨细胞和骨髓细胞中细胞因子的激素控制
  • 批准号:
    6098701
  • 财政年份:
    1999
  • 资助金额:
    $ 24.99万
  • 项目类别:

相似国自然基金

骨形态发生蛋白(Bone Morphogenetic Proteins,BMP)信号在脊髓损伤中枢神经性疼痛中的作用
  • 批准号:
    81070994
  • 批准年份:
    2010
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