Bone Properties in Hypoparathyroidism: Effects of PTH

描述(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，甲状旁腺激素(PTH)明显减少或缺乏循环。这主要是由于手术切除了所有的甲状旁腺组织或自身免疫性破坏了甲状旁腺。甲状旁腺激素的缺乏会导致血钙浓度降低，这可能是无症状的，也可能与低钙血症有关。甲状旁腺素缺乏还会导致骨骼的生化、密度、组织形态计量学、生物力学和细胞特性的重大异常。在过去5年的资助中，我们对PTH所监管的骨骼的这些方面有了深入的了解。这项建议寻求继续并扩大这一调查，以更全面地了解甲状旁腺激素的骨骼活动。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症(PHPT)，这是一种甲状旁腺激素过多的疾病。我们将使用同时的实验设计来研究这两种完全不同的甲状旁腺疾病，这两种疾病代表甲状旁腺激素不足/过剩光谱的两端。该模型具有更大的意义，因为我们将通过替换PTH(甲状旁腺功能减退)或通过甲状旁腺手术(PHPT)移除多余的PTH来纠正这两种甲状旁腺功能紊乱。通过研究甲状旁腺激素缺乏或过剩状态纠正前后的骨骼特征，我们可以赋予该分子特定的骨骼性质。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：双能量X射线吸收法、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)以及通过分析髂骨活组织来测量骨骼指数(组织形态计量学、5CT、基于同步加速器的5CT、定量背向散射电子成像和傅立叶变换红外光谱)。此外，还将测量骨转换标志物和循环中的成骨细胞前体细胞。这项提议的新知识将比那些与罕见疾病有关的知识产生更广泛的影响。相反，我们预计我们的结果将具有更广泛的影响，包括更好地理解甲状旁腺素对骨骼的正常控制以及甲状旁腺素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.