Estrogens, androgens, aging, and bone loss in males

男性雌激素、雄激素、衰老和骨质流失

基本信息

批准号：
8413601
负责人：
STAVROS C. MANOLAGAS
金额：
--
依托单位：
CENTRAL ARKANSAS VETERANS HLTHCARE SYS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8413601
关键词：
Adult Adverse effects Affect Aging Agreement Anabolism Androgens Antioxidants Apoptosis Attenuated Cell Survival Cells Chemosensitization Commit DNA Binding Defense Mechanisms Dendrimers Development Disease Enzymes Equilibrium Estradiol Estrogen Receptors Estrogens Excision Female Generations Genetic Transcription Gonadal Steroid Hormones Growth Homeostasis Longevity Maintenance Mediating Mesenchymal Molecular Muramidase Mus NF-kappa B Nuclear Organ Osteoblasts Osteoclasts Osteocytes Osteoporosis Ovarian Ovariectomy Oxidation-Reduction Oxidative Stress Pathway interactions Phosphorylation Production Reactive Oxygen Species Secondary to Seminal Vesicles Signal Transduction Skeleton Thick Weight Work attenuation base bone bone cell bone loss bone mass cathepsin K cell type dentin matrix protein 1 gain of function in vivo male osteoclastogenesis overexpression p66(ShcA) protein prevent progenitor protective effect receptor reproductive sex skeletal substantia spongiosa transcription factor

Adult Adverse effects Affect Aging Agreement Anabolism Androgens Antioxidants Apoptosis Attenuated Cell Survival Cells Chemosensitization Commit DNA Binding Defense Mechanisms Dendrimers Development Disease Enzymes Equilibrium Estradiol Estrogen Receptors Estrogens Excision Female Generations Genetic Transcription Gonadal Steroid Hormones Growth Homeostasis Longevity Maintenance Mediating Mesenchymal Molecular Muramidase Mus NF-kappa B Nuclear Organ Osteoblasts Osteoclasts Osteocytes Osteoporosis Ovarian Ovariectomy Oxidation-Reduction Oxidative Stress Pathway interactions Phosphorylation Production Reactive Oxygen Species Secondary to Seminal Vesicles Signal Transduction Skeleton Thick Weight Work attenuation base bone bone cell bone loss bone mass cathepsin K cell type dentin matrix protein 1 gain of function in vivo male osteoclastogenesis overexpression p66(ShcA) protein prevent progenitor protective effect receptor reproductive sex skeletal substantia spongiosa transcription factor

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项目摘要

DESCRIPTION (provided by applicant): Gonadectomy increases the generation of reactive oxygen species (ROS) in the murine skeleton and the adverse effects of the loss of ovarian or testicular function on bone can be prevented by anti-oxidants. Conversely, estrogens or non-aromatizable androgens decrease oxidative stress. The effects of estrogens result from DNA-binding independent actions of the ER1. In full agreement with such a mechanism, an estradiol dendrimer conjugate (EDC) that is not capable of stimulating the nuclear- initiated actions of ER1 reproduces the effects of estradiol on osteoclasts and osteoblasts ; and is as potent as estradiol in preventing oxidative stress and ovariectomy-induced bone loss, without affecting uterine weight. ER1 deletion in cells of the osteoclast lineage (expressing Lys-M) causes loss of cancellous, but not cortical, bone in female mice; while ER1 deletion from mesenchymal progenitors (Prx1 expressing cells) decreases cortical thickness in both females and males. Consistent with the above, ROS attenuate osteoblastogenesis and shorten the lifespan of osteoblasts and osteocytes. On the other hand ROS are required for osteoclast generation, function, and survival. Moreover, loss or gain of function of FoxOs - transcription factors that are an important defense mechanism against oxidative stress (OS) -dramatically alters skeletal homeostasis. Based on these findings it is hypothesized that similar to ER1-mediated effects of estrogens, AR-mediated effects of androgens decrease ROS generation in both osteoblasts and osteoclasts via cell autonomous mechanisms. Conversely, androgen deficiency increases ROS production in either cell type, and in the adult male skeleton this leads to loss of both cancellous and cortical bone. The protective effect of androgens on cancellous bone is mediated primarily via the osteoclast AR and results from decreased osteoclastogenesis and shortened osteoclast lifespan secondary to increased apoptosis. The protective effect of androgens on cortical bone is mediated via both the AR and the ER1 and is caused by attenuation of ROS-induced FoxO activation and the resulting potentiation of Wnt signaling and osteoblastogenesis. The EDC will be protective of cortical bone in gonadectomised males, as it is in females, without affecting male reproductive organs such as seminal vesicles. To advance these interrelated hypotheses, the contribution of cell autonomous effects of androgens on osteoblasts to skeletal homeostasis will be investigated by determining the effects of AR deletion from Prx1, Osx, or DMP1 expressing cells in the skeleton of male mice; and the effects of AR-mediated androgen signaling on ROS and FoxO-activated pathways in vivo and in osteoblastic cells isolated from these mice. Further, the contribution of cell autonomous effects of androgens on osteoclasts to skeletal homeostasis will be studied by determining the effects of AR deletion from LysM and Cathepsin K expressing cells in the skeleton of male mice; and the effects of AR-mediated androgen signaling on ROS-activated pathways in vivo and in osteoclastic cells isolated from these mice. Lastly, the contribution of the ER1 deletion from osteoblastic cells to skeletal homeostasis in the male and the bone sparing efficacy of the EDC in androgen deficient wild type adult male mice will be determined.

描述（由申请人提供）：性腺切除术会增加鼠骨骼中的活性氧（ROS）的产生，并且可以通过抗氧化剂预防卵巢损失或睾丸功能对骨骼的不利影响。相反，雌激素或不可芳香的雄激素会降低氧化应激。雌激素的影响是由ER1的DNA结合独立作用引起的。与这种机制完全一致，无法刺激ER1的核启动作用的雌二醇树突聚合物（EDC）再现雌二醇对成骨细胞和成骨细胞的影响；并且在预防氧化应激和卵巢切除术引起的骨质丧失方面与雌二醇一样有效，而不会影响子宫体重。破骨细胞谱系（表达Lys-M）细胞中的ER1缺失会导致雌性小鼠的取消但不骨骨骼损失。而间充质祖细胞（PRX1表达细胞）中的ER1缺失会降低女性和男性的皮质厚度。与上述，ROS衰减成骨细胞生成，并缩短成骨细胞和骨细胞的寿命。另一方面，ROS是破骨细胞生成，功能和生存所必需的。此外，FOXOS功能的丧失或增益 - 转录因子是针对氧化应激（OS）的重要防御机制 - 戏剧性地改变了骨骼稳态。基于这些发现，假设与雌激素的ER1介导的作用相似，雄激素的AR介导的伴有细胞自主机制在成骨细胞和破骨细胞中降低ROS的产生。相反，雄激素缺乏会增加任何一种细胞类型的ROS产生，而在成年男性骨骼中，这会导致取消和皮质骨的损失。雄激素对取消骨的保护作用主要是通过破骨细胞AR介导的，并导致破骨细胞生成减少并缩短了凋亡增加的破骨细胞寿命。雄激素对皮质骨的保护作用是通过AR和ER1介导的，是由ROS诱导的FOXO激活的衰减以及WNT信号传导和成骨细胞生成的增强引起的。 EDC将像在女性中一样保护性腺切除术中的皮质骨，而不会影响男性生殖器官，例如精液囊泡。为了推进这些相互关联的假设，将研究雄激素对成骨细胞对骨骼稳态的细胞自主作用的贡献，可以通过确定雄性小鼠骨骼中PRX1，OSX或DMP1表达细胞的AR缺失的影响；以及AR介导的雄激素信号传导对从这些小鼠分离的体内和成骨细胞中ROS和FOXO激活途径的影响。此外，通过确定雄性小鼠骨骼中表达细胞的AR缺失的影响，研究了雄激素对破骨细胞对骨骼稳态的细胞自主作用的贡献；以及AR介导的雄激素信号对体内和从这些小鼠分离的破骨细胞中ROS激活途径的影响。最后，将确定ER1缺失从成骨细胞对雄性的骨骼稳态的贡献，以及EDC在雄激素缺乏野生型成年雄性小鼠中的骨骼支撑功效的贡献。