Bone Properties in Hypoparathyroidism: Effects of PTH

描述（由申请人提供）：甲状旁腺功能减退症是一种罕见的人类骨骼疾病，其中甲状旁腺激素（PTH）显著降低或从循环中缺失。它主要是由于手术切除所有甲状旁腺组织或甲状旁腺的自身免疫性破坏。缺乏PTH导致血清钙浓度降低，这可能是无症状的或与低钙血症症状相关。甲状旁腺素缺乏还导致骨骼的生物化学、密度测定、组织形态测定、生物力学和细胞特性的主要异常。在过去5年的资助中，我们已经深入了解了PTH调控的骨骼的这些方面。这项建议旨在继续和扩大这一调查，以获得更全面的了解PTH的骨骼行动。为此，除了完成我们对甲状旁腺功能减退症的研究外，我们还将我们的实验方法应用于另一种人类骨骼疾病，原发性甲状旁腺功能亢进症（PHPT），一种PTH过量的疾病。我们将使用同期的实验设计来研究这两种完全不同的甲状旁腺疾病，这两种疾病代表了PTH不足/过量谱的两端。该模型实现了更大的意义，因为我们将纠正两种PTH疾病，无论是通过置换PTH（甲状旁腺功能减退）或通过甲状旁腺手术（PHPT）去除多余的PTH。通过研究PTH缺乏或过量状态校正前后的骨骼特征，我们可以将特定的骨骼特性分配给这种分子。最先进的方法包括评估骨骼的定量结构和动态特征的方法：双能X线吸收测定法，定量外周和中央计算机断层扫描（包括高分辨率pQCT、有限元分析、个体骨小梁分割分析、基于体素的QCT）和来自髂嵴骨活检分析的骨骼指数测量（组织形态学、5CT、基于同步加速器的5CT、定量背散射电子成像和傅里叶变换红外光谱）。此外，还将测量骨转换标志物和循环成骨细胞前体细胞。这项提案中的新知识将比与罕见疾病相关的知识具有更广泛的影响。相反，我们预计我们的研究结果将有更广泛的影响，包括更好地了解骨骼的正常控制PTH和PTH的合成代谢活性在绝经后骨质疏松症的治疗。 公共卫生相关性：这个项目旨在获得甲状旁腺激素，骨骼健康的关键调节器，有助于保持骨骼强壮的方法的新知识。

DESCRIPTION (provided by applicant): Hypoparathyroidism is an uncommon human skeletal disorder in which parathyroid hormone (PTH) is markedly decreased or absent from the circulation. It is due primarily to surgical removal of all parathyroid tissue or autoimmune destruction of the parathyroid glands. The absence of PTH leads to a reduction in the serum calcium concentration that can be asymptomatic or associated with symptoms of hypocalcemia. PTH deficiency also leads to major abnormalities in biochemical, densitometric, histomorphometric, biomechanical and cellular properties of the skeleton. Over the past 5 years of funding, we have gained insights into these aspects of the skeleton that are regulated by PTH. This proposal seeks to continue and to expand this investigation in order to gain more complete understanding of PTH's skeletal actions. To this end, in addition to completing our studies of hypoparathyroidism, we will apply our experimental approach to another human skeletal disorder, primary hyperparathyroidism (PHPT), a disorder of excessive PTH. We will use a cotemporaneous experimental design to investigate these two completely different parathyroid disorders, which represent opposite ends of the PTH insufficiency/excess spectrum. The model achieves greater significance because we will correct both PTH disorders, either by replacement of PTH (hypoparathyroidism) or by removal of excess PTH by parathyroid surgery (PHPT). By studying skeletal features before and after correction of states of PTH deficiency or excess, we can assign specific skeletal properties to this molecule. State-of-the-art approaches include methods to assess quantitative structural and dynamic features of the skeleton: dual energy X-ray absorptiometry, quantitative peripheral and central computed tomography (including high resolution pQCT, finite element analysis, Individual Trabecular Segmentation analysis, voxel- based QCT) and measurement of skeletal indices from analysis of iliac crest bone biopsies (histomorphometry, 5CT, synchrotron-based 5CT, quantitative back scattered electron imaging, and Fourier Transform Infrared Spectroscopy). In addition, bone turnover markers and circulating osteoblast precursor cells will be measured. The new knowledge from this proposal will have far wider implications than those associated with an uncommon disease. Rather, we anticipate our results will have far broader implications, including greater understanding both of the normal control of the skeleton by PTH and of the anabolic activity of PTH in the treatment of postmenopausal osteoporosis. PUBLIC HEALTH RELEVANCE: This project is designed to gain new knowledge of the means by which parathyroid hormone, a key regulator of skeletal health, helps to keep bones strong.