Nrf2 Activation for Treatment of Osteoporosis

在美国，骨质疏松症每年影响数百万患者。临床上可用的药物目前用于 治疗骨质疏松症和骨脆性综合征，仍是有限的。更年期和衰老过程中的雌激素丢失 导致活性氧化剂物种(ROS)的积累。长期卧床期间的机械卸载或 太空飞行还会增加细胞内ROS的产生，并导致骨质流失。虽然抗氧化剂，如 一氧化氮供体硝酸甘油和N-乙酰半胱氨酸对雌激素缺乏症有一定的积极作用 或卸载导致的骨丢失，还没有开发出针对骨代谢的有效抗氧化剂 疾病。我们最近发现了一个新的靶点，它调节抗氧化反应，并参与 负荷诱导的成骨和骨稳态。新的靶点是核因子红系2相关因子 2，称为Nrf2。之前的几项研究，包括我们的研究，都表明Nrf2有助于保护骨量 在正常和疾病条件下。最近，一种合成的NRF2激活剂，巴度松甲基(BARD)，它 已用于治疗糖尿病相关动脉粥样硬化和糖尿病慢性肾脏疾病 该药目前正处于第三阶段临床试验。我们的长期目标是确定是否将NRF2作为目标 药物干预可用于治疗骨质疏松症。我们的初步发现导致了这一点 应用支持通过药物干预在骨细胞中激活Nrf2的假设 通过降低ROS来预防或恢复因卸载或雌激素缺乏引起的骨丢失。我们建议 用C57BL/6小鼠和用Col2.3kB培育的Nrf2/-Flox小鼠进行了以下两个特异性靶向试验 COL1DMP1-Cre或α-8Kb-Cre小鼠分别诱导成骨细胞或骨细胞中NRF2的缺失。我们 将确定通过药物干预激活Nrf2是否可以防止或恢复骨丢失 卸载或雌激素缺乏的情况；我们还将确定细胞和分子机制 NRF2在骨骼组织中的信号转导。该项目的成功完成将展示NRF2的潜力 激活剂用于治疗骨质疏松症和鉴定Nrf2介导机制的骨细胞 参与骨形成的。该项目将进一步为骨细胞的机械敏感性和 骨骼适应性，并有可能发现骨质疏松症治疗的新靶点。

Osteoporosis affects millions of patients each year in the U.S. The clinically available agents, currently used to treat osteoporosis and bone fragility syndrome, are still limited. Estrogen loss at menopause and during aging leads to accumulation of reactive oxidant species (ROS). Mechanical unloading during long term bed rest or space flight also increase intracellular ROS production and cause bone loss. Although antioxidants, such as nitric oxide donor nitroglycerin and N-acetyl-cysteine have shown some positive effects on estrogen deficiency or unloading induced bone loss, no potent antioxidants have been developed to target on bone metabolic diseases. We have recently identified a novel target that regulates anti-oxidative response and is involved in load-induced osteogenesis and bone homeostasis. The novel target is nuclear factor erythroid 2-related factor 2, known as Nrf2. Several previous studies including ours have shown Nrf2 helps to preserve bone mass during normal and disease conditions. Recently, a synthetic Nrf2 activator, Bardoxolone Methyl (BARD), which has been used to treat diabetes associated atherosclerosis and diabetic chronic kidney diseases in animal models, is currently in Phase III clinical trials. Our long-term goal is to determine whether targeting Nrf2 by pharmacological intervention can be used to treats osteoporosis. Our preliminary findings leading to this application support the hypothesis that Nrf2 activation in osteocytes by pharmacological intervention may prevent or restore bone loss caused by unloading or estrogen deficiency through reducing ROS. We propose the following two specific aims using C57BL/6 mice as well as the Nrf2-/- floxed mice bred with Col2.3kB Col1α1-Cre or DMP1-8kb-Cre mice toward deletion of Nrf2 in osteoblastic cells or osteocytes, respectively. We will determine whether activation of Nrf2 by pharmacological intervention prevents or restores bone loss in unloading or estrogen deficient conditions; We will also determine the cellular and molecular mechanisms of Nrf2 signaling in skeletal tissues. Successful completion of this project will demonstrate potential of Nrf2 activator used to treat osteoporosis and identify the bone cells responsible for Nrf2-mediated mechanisms involved in bone formation. The project will further provide new insights in mechanosensitivity of bone cells and skeletal adaptation, and has potential to discover novel targets for osteoporosis therapy.