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
• 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
• 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/8598056
• 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

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)： 性腺切除会增加小鼠骨骼中活性氧物种(ROS)的生成，卵巢或睾丸功能丧失对骨骼的不利影响可以通过抗氧化剂来预防。相反，雌激素或非芳香化雄激素可减少氧化应激。雌激素的作用是通过ER1与DNA结合的非依赖作用产生的。与这一机制完全一致的是，不能刺激ER1核启动活动的雌二醇树状大分子结合物(EDC)复制了雌二醇对破骨细胞和成骨细胞的影响；在预防氧化应激和卵巢切除引起的骨丢失方面与雌二醇一样有效，而不影响子宫重量。破骨细胞系细胞中ER1的缺失(表达Lys-M)会导致雌性小鼠松质骨的丢失，但不会导致皮质骨的丢失；而间充质祖细胞(表达PRX1的细胞)中的ER1缺失会降低雌性和雄性小鼠的皮质厚度。与上述一致，ROS抑制成骨细胞的形成，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功能的丧失或增加-转录因子是对抗氧化应激(OS)的重要防御机制-显著改变骨骼的动态平衡。根据这些发现，推测与雌激素的ER1介导的作用类似，雄激素的AR介导的作用通过细胞自主机制减少成骨细胞和破骨细胞中ROS的产生。相反，雄激素缺乏会增加任何一种细胞中ROS的产生，在成年男性骨骼中，这会导致松质骨和皮质骨的丢失。雄激素对松质骨的保护作用主要是通过破骨细胞AR介导的，其结果是破骨细胞生成减少，破骨细胞寿命缩短，继而增加了细胞凋亡。雄激素对皮质骨的保护作用是通过AR和ER1介导的，其机制是通过抑制ROS诱导的FoxO活化，从而增强Wnt信号和成骨细胞的形成。在性腺切除的男性中，EDC将保护皮质骨，就像在女性中一样，而不会影响男性的生殖器官，如精囊。为了推进这些相互关联的假说，将通过确定雄性小鼠骨骼中表达PRX1、OSX或DMP1的细胞中AR缺失的影响，以及AR介导的雄激素信号对体内ROS和FoxO激活途径以及这些小鼠分离的成骨细胞中ROS和FoxO激活途径的影响，来研究雄激素对成骨细胞的细胞自主作用对骨骼动态平衡的贡献。此外，通过确定雄性小鼠骨骼中表达组织蛋白酶K和LysM的细胞中AR缺失的作用，以及AR介导的雄激素信号对体内和这些小鼠分离的破骨细胞中ROS激活途径的影响，将研究雄激素对破骨细胞的细胞自主作用对骨骼动态平衡的贡献。最后，将确定成骨细胞ER1缺失对雄性骨骼稳态的贡献，以及EDC在雄激素缺乏的成年雄性小鼠中的骨保存效果。