Renal Osteodystrophy and Vascular Calcification

描述（由申请人提供）：慢性肾脏疾病（CKD）及其并发症的病理生理学的最新进展引起了对高磷血症、血管钙化和CKD过度死亡率之间关系的关注。最近的一项研究表明，羟基磷灰石的骨骼沉积在CKD的血清磷酸盐水平中起着重要作用。这一概念是从进一步定义肾脏作为内分泌器官在不同组织功能中相互作用的研究中出现的。两个新的病理生理学原则已经出现在这些最近的研究，将在本申请中进行测试。第一个新的原理是慢性肾损伤直接损害骨骼愈合。第二，肾性骨营养不良和血管钙化部分与高磷血症直接相关。到目前为止，肾性骨营养不良被认为是由于高磷酸盐血症和骨化三醇缺乏引起的低钙血症引起的继发性甲状旁腺功能亢进。然而，最近，当钙，磷甲状旁腺激素和骨化三醇的异常在CKD中被避免时，该疾病已被证明与粘附性骨疾病有关。将通过本申请中的研究进行检验的从该观察结果得出的假设是，CKD损害骨骼骨骼的抗氧化性，并且这发生在二价离子代谢异常之前，甚至参与其产生。第一个目标的研究旨在进一步确立这一原则，并确定与CKD相关的骨骼合成代谢损失的病理生理机制。正在开发的CKD治疗剂骨形态发生蛋白-7（BMP-7）是肾性骨营养不良和血管钙化的有效治疗方法。在本申请中寻求该药剂的作用机制，这将为治疗和预防CKD及其并发症提供新的见解和新的治疗靶点。最近的研究发现，在代谢综合征（胰岛素抵抗、肥胖、高血压和血脂异常）的动物模型中，骨形成显著减少。当在这些动物中产生消融性CKD时，尽管存在继发性甲状旁腺功能亢进，骨骼结局仍为粘连性骨病。由于CKD在该模型中也刺激血管钙化，这些研究提出了肾性骨营养不良和血管钙化直接相关的假设。第二个特定目标的研究检验了这样一个假设，即通过增加骨形成产生的血清磷减少导致血管钙化减少。申请的具体目的是：1。明确CKD和代谢综合征引起的骨骼肌张力丧失的机制; 2.阐明BMP-7在慢性肾脏病血管钙化中的作用机制; 3.证明高脂饮食和Wnt信号之间的相互作用，以及Wnt信号和BMP-7在CKD刺激的血管平滑肌中的相互作用。

DESCRIPTION (provided by applicant): Recent advances in the pathophysiology of chronic kidney disease (CKD) and its complications have called attention to the relationship between hyperphosphatemia, vascular calcification and excess mortality of CKD. A recent discovery demonstrates that skeletal apposition of hydroxyapatite plays an important role in the levels of serum phosphate in CKD. This concept has emerged from studies that further define the role of the kidney as an endocrine organ interacting in the function of different tissues. Two new pathophysiologic principles have emerged from these recent studies that will be tested in this application. The first new principle is that chronic renal injury directly impairs skeletal anabolism. The second is that renal osteodystrophy and vascular calcification are directly linked in part by hyperphosphatemia. Until now, renal osteodystrophy was thought to result from secondary hyperparathyroidism produced by hypocalcemia due to hyperphosphatemia and calcitriol deficiency. Recently, however, when abnormalities of calcium, phosphorus parathyroid hormone and calcitriol were avoided in CKD, the disease has been shown to be associated with adynamic bone disorder. The hypothesis deriving from this observation that will be tested by studies in this application is that CKD impairs skeletal anabolism, and that this occurs before abnormalities in divalent ion metabolism and even participates in their production. Studies in the first aim are designed to further establish this principle and determine the pathophysiologic mechanism of anabolic loss in the skeleton associated with CKD. A therapeutic agent in development for CKD, bone morphogenic protein-7 (BMP-7), is an effective treatment for renal osteodystrophy and vascular calcification. The mechanisms of action of this agent are sought in this application which should provide new insights and new therapeutic targets for treatment and prevention of CKD and its complications. Recent studies have discovered a significant reduction of bone formation in an animal model of the metabolic syndrome (insulin resistance, obesity, hypertension and dyslipidemia). When ablative CKD was produced in these animals, the skeletal outcome was the adynamic bone disorder despite the presence of secondary hyperparathyroidism. Since CKD also stimulated vascular calcification in this model, these studies raise the hypothesis that renal osteodystrophy and vascular calcification are directly linked. Studies in the second specific aim test the hypothesis that reductions in the serum phosphorus produced by increasing bone formation result in reduced vascular calcification. The specific aims of the application are: 1. Determine the mechanisms of the loss of skeletal anabolism induced by CKD and the metabolic syndrome; 2. Demonstrate the mechanisms of BMP-7 actions in the vascular calcification produced by chronic kidney disease; 3. Demonstrate the interactions between high fat diets and Wnt signaling on one hand, and Wnt signaling and BMP-7 on the other in the vascular smooth muscle stimulated by CKD.