Circulating Osteoblast Lineage Cells in Hypoparathyroidism

描述（由申请人提供）： 甲状旁腺功能减退症是一种罕见的疾病，其中甲状旁腺激素（PTH）是缺乏循环。如果没有PTH，骨骼不会进行正常的骨转换，这是一个对健康骨骼重塑至关重要的过程。我的K23的重点是测试PTH对正常骨骼结构和功能至关重要的假设。我正在研究30名甲状旁腺功能减退患者在PTH替代治疗前后的骨质量。我的第一个目标是彻底描述甲状旁腺功能减退状态下的骨骼特征。迄今为止，通过对19例甲状旁腺功能减退症患者进行经皮髂嵴骨活检，我在实现这一最初目标方面取得了重大进展。初步数据表明，甲状旁腺功能减退症的骨转换受到严重抑制，骨质量指标明显异常。K23的第二个目标是对甲状旁腺功能减退的受试者给予PTH，并测试在PTH缺乏状态下表征的骨异常特性如何归因于PTH缺乏。我目前正在对19名研究受试者进行PTH（1-84）给药。初步数据表明，甲状旁腺素替代恢复骨转换正常。随着项目的进行，追求项目目标的其他方面，我预计骨质量的相应改善将得到证实。最初申请的一个未提出研究的领域涉及可以解释PTH调节骨转换和改善骨质量的作用的潜在机制。一个有吸引力的机制是PTH提供新的成骨细胞，可用于增强骨重建。最近，已经观察到成骨细胞谱系细胞可以在外周血中检测到大量。为了扩大K23的研究目标，我将测试的假设，PTH增加循环成骨细胞谱系细胞的数量时，与甲状旁腺功能减退症的受试者。因此，除了继续追求K23奖的最初目标外，我将进行一项试点研究，以确定甲状旁腺功能减退是否与循环成骨细胞谱系细胞减少有关，以及PTH替代是否提供了更多的这些细胞供应。我希望在这一新的研究途径中获得的数据将导致进一步的研究，以更机械地描述PTH如何影响成骨细胞谱系特性，不仅在甲状旁腺功能减退症中，而且在原发性甲状旁腺功能亢进症和PTH治疗骨质疏松症后。这个项目将继续和扩展我正在进行的调查甲状旁腺激素的行动，以改善骨质。计划进行更多的研究，以获得关于一种有吸引力的机制的新信息，以解释这些观察结果，即增加成骨细胞或骨生成细胞的可用性的效果。

DESCRIPTION (provided by applicant): Hypoparathyroidism is an uncommon disorder in which parathyroid hormone (PTH) is absent from the circulation. Without PTH, the skeleton does not undergo normal bone turnover, a process that is essential for healthy skeletal remodeling. The focus of my K23 is to test the hypothesis that PTH is essential for normal skeletal structure and function. I am studying bone quality in 30 patients with hypoparathyroidism before and after PTH replacement. My first goal is to characterize thoroughly the skeleton in the hypoparathyroid state. I have made significant progress toward this original goal by performing percutaneous iliac crest bone biopsies on 19 subjects to date with hypoparathyroidism. The preliminary data indicate that bone turnover in hypoparathyroidism is profoundly suppressed and that indices of bone quality are markedly abnormal. The second goal of the K23 is to administer PTH to subjects with hypoparathyroidism and to test how the abnormal properties of bone that were characterized in the PTH-deficient state could be attributed to the lack of PTH. I am currently administering PTH(1-84) to 19 study subjects. The preliminary data suggest that PTH replacement is restoring bone turnover to normal. As the project proceeds, pursuing other aspects of the goals of the project, I expect that concomitant improvements in bone quality will be demonstrable. One area of the original application that was not proposed for study relates to underlying mechanisms that can account for PTH's actions to regulate bone turnover and improve bone quality. One attractive mechanism is that PTH is providing new osteoblasts that become available for enhanced bone remodeling. Recently, it has been observed that osteoblast lineage cells can be detected in significant numbers in the peripheral blood. To expand the research objectives of the K23, I will test the hypothesis that PTH increases the number of circulating osteoblast lineage cells when administered to subjects with hypoparathyroidism. Thus, in addition to continuing to pursue the original goals of the K23 award, I will conduct a pilot study to determine whether hypoparathyroidism is associated with reduced circulating osteoblast lineage cells and whether PTH replacement provides a greater supply of these cells. I expect that the data acquired in this new avenue of research will lead to further studies to delineate more mechanistically how PTH affects osteoblast lineage properties, not only in hypoparathyroidism, but also in primary hyperparathyroidism and after PTH treatment for osteoporosis. This project will continue and extend my ongoing investigation into the actions of parathyroid hormone to improve bone quality. Additional studies are planned to gain new information about an attractive mechanism to account for these observations, namely an effect to increase the availability of osteoblast, or bone-building, cells.