Renal Osteodystrophy and Vascular Calcification

描述(申请人提供)：慢性肾脏病(CKD)及其并发症的病理生理学的最新进展引起了人们对高磷血症、血管钙化和CKD超额死亡率之间的关系的关注。最近的一项发现表明，羟基磷灰石的骨骼堆积在慢性肾脏病患者的血磷水平中起着重要作用。这一概念是从进一步确定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产生的。两个新的病理生理学原理已经从这些最近的研究中出现，将在这一应用中进行测试。第一个新原理是慢性肾损伤直接损害骨骼合成代谢。第二，肾性骨营养不良和血管钙化在一定程度上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症。然而，最近，当CKD患者避免了钙、磷、甲状旁腺激素和骨化三醇的异常时，这种疾病被证明与动态骨病有关。从这一观察中得出的假说将被这一应用中的研究所验证，即CKD损害骨骼合成代谢，并且这种情况发生在二价离子代谢异常之前，甚至参与了它们的产生。第一个目标的研究旨在进一步确立这一原则，并确定CKD相关骨骼中合成代谢丢失的病理生理机制。骨形态发生蛋白-7(BMP-7)是治疗肾性骨营养不良和血管钙化的有效药物。探讨该药的作用机制，为CKD及其并发症的治疗和预防提供新的思路和新的治疗靶点。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症，但骨骼的结局是动态的骨病。由于CKD在该模型中也刺激了血管钙化，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验证了一种假设，即增加骨形成所产生的血清磷的减少会导致血管钙化的减少。其应用的具体目的是：1.明确CKD导致骨骼合成代谢丧失和代谢综合征的机制；2.阐明BMP-7在慢性肾脏疾病引起的血管钙化中的作用机制；3.一方面阐明高脂饮食与Wnt信号之间的相互作用，另一方面证明CKD刺激的血管平滑肌中Wnt信号与BMP-7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.