Common Inflammation Pathways between Aging and Hypertension That Weaken Bone

项目摘要/摘要 骨质疏松症诊断不足，治疗不足。我们必须开发新的工具来进行早期检测 以及减少伴随年龄增长的脆性骨折数量的治疗策略。全身性高血压 是另一种通常与骨质疏松症并存的衰老疾病，可能使个人容易患上 疾病。在这个多学科的项目中，我们将研究高血压之间的共同分子基础 以及在衰老过程中削弱骨骼的骨质疏松症。我们的初步数据显示实验性高血压 老鼠的参与与骨骼强度的显著下降有关，这在一定程度上是通过产生 骨髓中的集落刺激因子1(CSF1)。该项目的第一个目标将是检验这一假设 增强的内皮细胞变形和升高的血压促进了与年龄相关的骨量下降 力量。我们将使用细胞培养实验，在实验中内皮细胞动态伸展到下面 人单核细胞是否含有外源重组蛋白以确定其释放的因子是否 激活的内皮细胞促进破骨细胞分化。此外，我们还将降低老龄小鼠的血压 并确定这是否通过减少有利于骨吸收的炎性细胞因子来提高骨骼强度。这个 第二个目标是验证这样一种假设，即交感神经张力在衰老和高血压时增强会促进 免疫激活和骨质流失。我们是使用一种名为 设计师受体被设计师药物和局部去神经技术所独有地激活。因此，我们将 增加交感神经张力，以确定这是否模拟与年龄相关的骨强度下降和下降 交感神经音调，以确定这是否可以防止高血压和衰老导致的骨强度丧失。第三 目标是在成年小鼠中删除内皮CSF1基因，以牢固地确立内皮作为媒介的地位 骨质疏松症。最后，我们先前的工作已经确立了细胞因子白介素17A在 高血压和其他研究表明，它在雌激素撤除引起的骨丢失中起着关键作用。 (更年期)。因此，我们将产生突变小鼠，允许成年小鼠删除IL17受体A 并确定这是否可以防止与高血压相关的骨质流失。作为翻译目标，我们将对待老年人或 具有对照抗体和载体、中和抗CSF1抗体或IL-17RA的高血压小鼠 对抗，并确定这些策略是否可以提高骨骼强度。在所有目标中，我们都会监测血压 和骨量，2)评估骨髓中的免疫细胞特征，以及3)全面表征骨骼 强度包括韧性和其他骨质量测量。通过了解高血压是如何影响 老化背景下的骨髓和作为一个由不同技能组成的协作研究团队工作 SET，可以确定新的治疗策略，以防止与年龄相关的骨折风险增加。

Project Summary / Abstract Osteoporosis is under diagnosed and under treated. It is essential that we develop novel tools for early detection and treatment strategies to reduce the number of fragility fractures that accompany aging. Systemic hypertension is another disease of aging that commonly co-exists with osteoporosis and likely predisposes individuals to the disease. In this multidisciplinary project, we will investigate a common molecular basis between hypertension and osteoporosis that weakens bone during aging. Our preliminary data indicate that experimental hypertension involving mice is associated with a striking loss in bone strength, which is mediated in part by the production of colony stimulating factor 1 (CSF1) in the bone marrow. The first goal of the project will be to test the hypothesis that enhanced endothelial cell deformation and elevated blood pressure promote the age-related decline in bone strength. We will employ cell culture experiments in which endothelial cells are dynamically stretched below human monocytes with and without exogenous recombinant proteins to determine if factors released by the activated endothelium promote osteoclast differentiation. In addition, we will lower blood pressure of aged mice and determine if this improves bone strength by reducing inflammatory cytokines that favor bone resorption. The second goal will be to test the hypothesis that enhanced sympathetic tone in aging and hypertension promotes immune activation and bone loss. We are experts at modulating sympathetic tone using a technique called Designer Receptor Exclusively Activated by Designer Drugs and by local denervation techniques. Thus, we will increase sympathetic tone to determine if this mimics the age-related decline in bone strength and decrease sympathetic tone to determine if this prevents hypertension and aging-induced loss in bone strength. The third goal will be to delete the endothelial CSF1 gene in adult mice to firmly establish the endothelium as a mediator of osteoporosis. Finally, our prior work has established a critical role of the cytokine interleukin (IL) 17A in hypertension, and others have shown that it plays a critical role in bone loss due estrogen withdrawal (menopause). We will therefore generate mutant mice that will allow deletion of IL17 receptor A in adult mice and determine if this prevents hypertension-related bone loss. As a translational goal, we will treat aged or hypertensive mice with a control antibody and vehicle, a neutralizing anti-CSF1 antibody, or an IL-17RA antagonist and determine if these strategies improve bone strength. In all aims we will 1) monitor blood pressure and bone mass, 2) assess immune cell profiles in the bone marrow, and 3) comprehensively characterize bone strength including toughness and other bone quality measurements. By understanding how hypertension affects bone marrow in the context of aging and by working as a collaborative research team comprised of different skill sets, new therapeutic strategies can be identified to prevent the age-related increase in fracture risk.