Improving bone mass and quality in comorbid diabetes and chronic kidney disease

项目总结 糖尿病和慢性肾脏疾病(CKD)一直位居美国前十大慢性疾病之列 在流行率和死亡率方面，这些国家的情况也有所不同。美国退伍军人患糖尿病和慢性肾脏病的速度令人震惊， 与普通人群相比，退伍军人合并疾病的发生率是普通人群的两倍。这两种疾病都让患者 在骨折风险增加的情况下，当骨折发生时，患者的死亡风险比其他患者更大 人口。骨骼疾病的治疗通常解决骨量或组织质量方面的缺陷，这是 在合并CKD和糖尿病的情况下，如果两者都存在已知的缺陷，可能是不够的。尽管他们 不断增加的合并症和对骨骼的有害影响，它们之间的骨骼相互作用 由于缺乏合并疾病的动物模型和常规排斥患者，仍未被探索 来自临床药物试验的糖尿病和/或慢性肾脏病。这个项目的目标是研究骨骼之间的相互作用 糖尿病和慢性肾脏病，并确定有效的联合骨骼治疗方法。使用我们的新型组合模型 糖尿病和慢性肾脏病，我们将检验增加骨量同时改善的中心假设 使用综合疗法的组织质量将增加骨骼的机械强度，改善抗折性，以及 逆转晚期糖尿病+慢性肾脏病对骨骼的不良影响。为了实现这一目标，我们将用我们的小说 糖尿病和慢性肾脏病的联合模型研究分子、生化和成分的变化 具有多尺度的结构和力学性能。目标1将调查合并疾病的影响作为 发病年龄和病程的作用。我们的实验室已经建立了糖尿病的联合模型 (链脲佐菌素)和CKD(腺嘌呤)，它可以独特地改变小鼠的骨骼特性。4个实验将是 使用，在幼鼠或老年鼠中诱发疾病，然后允许疾病在短期或更长时间内进展 持续时间。主要结果将包括纵向胰岛素和血糖监测、糖化血红蛋白、胰岛素和血糖 耐受性试验、胰岛β细胞质量和肾脏生化。骨骼的结果将包括生化 周转和疾病的标志物，结构成像，骨形成/吸收组织学，以及一套 多尺度力学和成分特性。这些实验将阐明糖尿病和慢性肾脏病是如何 对骨骼的影响与性别、年龄和病程有关。在目标2中，我们将确定骨骼 机械负荷(改善骨量)联合雷洛昔芬治疗晚期疾病的疗效观察 (RAL--改善组织的水合作用和质量)。我们已经证明了一种FDA批准的治疗药物Ral 骨，特别是以细胞和雌激素不依赖的方式有益于骨材料特性。终点将 与目标1中的相同，包括共聚焦拉曼光谱和纳米压痕来表征 与老年人相比，干预期间形成的骨骼的矿物质和胶原特性/力学 骨头。为了增加目标3中的翻译价值，我们将确定药物综合疗法的效果 起病于糖尿病合并慢性肾脏病的晚期。这项工作将挑战这样一种观点，即 骨骼上的疾病等于各部分之和，将对我们的高危人群产生积极影响--老兵 通过提供新的方法来预防或治疗与糖尿病和慢性肾脏病相关的骨骼缺陷。

PROJECT SUMMARY Diabetes and chronic kidney disease (CKD) consistently rank among the top ten chronic conditions in the United States in terms of prevalence and mortality. US veterans develop diabetes and CKD at an alarming rate, and comorbidity is twice as common in veterans compared with the general population. Both diseases put patients at increased risk of fracture and when fractures occur, patients are at a greater risk of death compared to other populations. Treatments for skeletal disease typically address deficits in either bone mass or tissue quality, which may be insufficient in cases of combined CKD and diabetes where there are known deficits in both. Despite their increasing comorbidity and well-established detrimental impacts on the skeleton, their skeletal interaction remains unexplored due to a lack of combined disease animal models and routine exclusion of patients with diabetes and/or CKD from clinical drug trials. The goal of this project is to study skeletal interactions between diabetes and CKD and to identify effective combination skeletal treatments. Using our novel combined model of diabetes and CKD, we will test the central hypothesis that increasing bone mass while concurrently improving tissue quality using combined therapies will increase bone mechanical strength, improve fracture resistance, and reverse adverse skeletal effects of late-stage diabetes+CKD. To achieve this goal, we will use our novel combined model of diabetes and CKD to investigate molecular, biochemical, and compositional changes coupled with multiscale structural and mechanical properties. Aim 1 will investigate the effects of combined disease as a function of age of onset and disease duration. Our lab has established a combined model of diabetes (streptozotocin) and CKD (adenine) that uniquely alters skeletal properties in young mice. 4 experiments will be used, inducing disease in either young or aged mice, and then allowing disease to progress for a short or longer duration. Key outcomes will include longitudinal insulin and glucose monitoring, HbA1c, insulin and glucose tolerance tests, pancreatic beta cell mass, and renal biochemistries. Skeletal outcomes will include biochemical markers of turnover and disease, structural imaging, bone formation/resorption histology, and a suite of multiscale mechanical and compositional properties. These experiments will clarify how diabetes and CKD impact the skeleton as a function of sex, age, and disease duration. In Aim 2, we will determine the skeletal impacts of treatment in late-stage disease utilizing mechanical loading (to improve bone mass) and Raloxifene (RAL – to improve tissue hydration and quality). We have shown that RAL, an FDA-approved agent for treating bone, specifically benefits bone material properties in a cell- and estrogen-independent manner. End points will be the same as those in Aim 1, including colocalized Raman spectroscopy and nanoindentation to characterize the mineral and collagen properties/mechanics of bone formed during the interventions compared with older bone. To increase translational value in Aim 3, we will determine the effects of pharmaceutical polytherapies initiated in late-stage combined diabetes and CKD. This work will challenge the idea that the effect of combined disease on the skeleton is equal to the sum of the parts and will have a positive impact in our at risk-veteran population by providing new ways to prevent or treat skeletal deficits associated with diabetes and CKD.