MODELING BONE FORMATION AND 125 VITAMIN D IN HUMORAL HYPERCALCEMIA OF MALIGNANCY

描述（由申请人提供）：恶性肿瘤体液性高钙血症（HHM）和原发性甲状旁腺功能亢进（HPT）在许多方面相似，这些相似之处自1980年代后期发现甲状旁腺功能亢进（PTHrP）以来就很明显。另一方面，两种综合征之间仍存在两个未解之谜：HPT与成骨细胞活性增加和血浆1,25(OH)2D增加有关，而HHM则相反。这是令人惊讶的，因为目前的理论表明PTH和PTHrP通过共同的PTH1受体发出相似的信号。最近，我们在健康人身上进行了两到四天的PTH和PTHrP直接对比输注，以评估正常健康人成骨形成和1,25(OH)2D的调节。这些研究得出了令人惊讶的观察结果：首先，与预期的对1,25(OH)2D的等效作用相反，稳态连续输注PTH和PTHrP对1,25(OH)2D产生了非常不同的影响。这表明PTH和PTHrP在人体肾脏中通过PTH1R信号的方式并不相同。第二，尽管HPT的骨形成特征有所增加，尽管每天间歇注射PTH和PTHrP会导致骨形成增加，但在健康的人类志愿者中，48-96小时输注PTH和PTHrP会导致骨形成明显受到抑制。这些观察结果强调了一个事实，即关于甲状旁腺激素和甲状旁腺thrp如何调节骨形成和骨吸收，我们还有很多需要了解的。因此，本建议的具体目标是：

DESCRIPTION (provided by applicant): Humoral hypercalcemia of malignancy (HHM) and primary hyperparathyroidism (HPT) resemble one another n many ways, and these similarities have been apparent since the discovery of PTHrP in the late 1980's. On the other hand, two unresolved enigmatic differences remain between the two syndromes: HPT is associated with increases in osteoblast activity and increases in plasma 1,25(OH)2D, whereas HHM is associated with the reverse. This is surprising, because current dogma indicates that both PTH and PTHrP signal similarly via the common PTH1 receptor. Recently, we have performed directly comparative infusions of PTH and PTHrP in healthy human subjects over two to four days to evaluate the regulation of osteoblastic bone formation and 1,25(OH)2D in normal healthy subjects. These studies make surprising observations: First, in contrast to the anticipated equivalent effects on 1,25(OH)2D, steady-state, continuous infusions of PTH and PTHrP produce very different effects on 1,25(OH)2D. This suggests that the manner in which PTH and PTHrP signal via the PTH1R in human kidney is not identical. Second, despite the increase in bone formation characteristic of HPT, and despite the increase in bone formation induced by intermittent daily injections of PTH and PTHrP, 48-96 hour infusion of both PTH and PTHrP lead to marked suppression of bone formation in healthy human volunteers. These observations highlight the fact that we have much to learn about how PTH and PTHrP regulate bone formation and bone resorption. The Specific Aims of the current proposal are therefore: 1. To define how the temporal profile of PTH and PTHrP administration influences the anabolic skeletal response in humans 2. To determine how long-term continuous or pulsatile PTH and/or PTHrP influences plasma 1,25(OH)2D regulation in humans. These studies will be the first long-term (two week) sustained PTH or PTHrP infusion studies in humans, and are designed to elucidate the mechanisms of the mechanisms underlying the anabolic effects of PTH and PTHrP, and to fully define the apparent differences in PTH1R coupling to renal 1-alpha hydroxylase.