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）明显减少或从循环中消失。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破坏。甲状旁腺激素的缺失导致血清钙浓度的降低，这可能是无症状的或与低钙血症的症状相关。甲状旁腺激素缺乏还会导致骨骼的生化、密度、组织形态学、生物力学和细胞特性的重大异常。在过去5年的资助中，我们已经深入了解了由甲状旁腺调节的骨骼的这些方面。本建议旨在继续和扩大这一调查，以便更全面地了解甲状腺激素的骨骼作用。为此，除了完成我们对甲状旁腺功能低下的研究外，我们还将把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（PHPT），一种过度甲状旁腺激素的疾病。我们将采用同期实验设计来研究这两种完全不同的甲状旁腺疾病，它们代表着甲状旁腺功能不全/过度谱系的两端。该模型具有更大的意义，因为我们将纠正这两种PTH疾病，要么通过替换PTH（甲状旁腺功能减退），要么通过甲状旁腺手术（PHPT）去除多余的PTH。通过研究甲状旁腺激素缺乏或过量状态纠正前后的骨骼特征，我们可以将特定的骨骼性质分配给该分子。最先进的方法包括评估骨骼定量结构和动态特征的方法：双能x射线吸收仪，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，个体小梁分割分析，基于体素的QCT），以及来自髂骨活检分析的骨骼指标测量（组织形态学测量，5CT，基于同步辐射的5CT，定量背散射电子成像和傅里叶变换红外光谱）。此外，骨转换标志物和循环成骨细胞前体细胞将被测量。这项提议带来的新知识将比那些与罕见疾病相关的知识具有更广泛的意义。相反，我们预计我们的结果将具有更广泛的意义，包括更好地理解PTH对骨骼的正常控制以及PTH在治疗绝经后骨质疏松症中的合成代谢活性。

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.