Effects of PTH Excess on Cortical and Cancellous Bone

描述（由申请人提供）：甲状旁腺激素（PTH）对骨骼的影响是复杂的，知之甚少。甲状旁腺激素对骨骼有分解代谢和合成代谢作用。一方面，慢性PTH水平升高，如中重度甲状旁腺功能亢进患者，或持续输注，具有分解代谢作用，在皮质骨中尤其明显。相反，在轻度甲状旁腺功能亢进患者中，或间歇性给予甲状旁腺激素，有合成代谢作用，主要在松质骨中明显。然而，甲状旁腺激素（PTH）对皮质骨和松质骨、轻度甲状旁腺功能亢进和重度甲状旁腺功能亢进、连续给药和间歇给药的不同作用机制尚不清楚。研究甲状旁腺激素双重作用机制的主要障碍是缺乏有效的模型系统。我们目前的大部分理解都是基于体外系统。然而，这些系统缺乏充分评估甲状旁腺激素诱导的分子和细胞变化对骨形成和吸收的生理调节以及骨的建筑和生物力学改变的影响的能力。提出的研究将利用最近开发的甲状旁腺功能亢进转基因小鼠模型来克服这些局限性。到10个月大时，这些小鼠发展为轻度甲状旁腺功能亢进，最终发展为慢性中度至重度甲状旁腺功能亢进。第一个特异性目标将描述轻度和中度/重度甲状旁腺功能亢进状态下甲状旁腺激素过量对松质骨和皮质骨的定量和定性影响。第二个特定目标将研究轻度和重度HPT对小梁成骨细胞增殖、成骨细胞凋亡和破骨细胞形成的影响。这些研究的结果将是体内模型系统的特征，可以在未来的研究中有效地用于研究甲状旁腺激素对骨骼的合成代谢和分解代谢作用的机制。鉴于最近使用甲状旁腺激素治疗骨质疏松症，迫切需要更好地了解其作用机制。

DESCRIPTION (provided by applicant): The effects of parathyroid hormone (PTH) on the skeleton are complex and poorly understood. PTH can have both catabolic and anabolic effects on bone. On the 1 hand, chronic elevated PTH levels, as in patients with moderate to severe hyperparathyroidism, or with continuous infusion, has catabolic effects, particularly evident in the cortical bones. In contrast, in patients with mild hyperparathyroidism, or intermittent administration of PTH, has an anabolic effect, predominantly evident in the cancellous bone. However, the mechanisms that underlie the differential effects of PTH--on the cortical versus cancellous skeleton, in states of mild versus severe hyperparathyroidism, or with continuous versus intermittent administration--are yet unclear. A major hurdle in studying the mechanisms for PTH's dual actions has been the lack of an effective model system. Much of our current understanding has been based on in vitro systems. However, such systems lack in their ability to fully evaluate the influence of PTH-induced molecular and cellular changes on physiological regulation of bone formation and resorption and on architectural and biomechanical alterations in bone. The proposed studies will exploit a recently developed transgenic mouse model of hyperparathyroidism to overcome these limitations. By the age of 10 months, these mice develop mild hyperparathyroidism, which eventually progresses to chronic moderate to severe hyperparathyroidism. The first Specific Aim will characterize quantitative and qualitative effects of PTH excess on the cancellous and cortical bones in states of mild and moderate/severe hyperparathyroidism. The second Specific Aim will examine the effects of mild and severe HPT on trabecular osteoblast proliferation, osteoblast apoptosis and osteoclast formation. The outcome of these studies will be the characterization of an in vivo model system that can be effectively used in future studies to investigate the mechanisms of both, the anabolic and catabolic effects of PTH on bone. Given the recent use of PTH to treat osteoporosis, there is a critical need to better understand the mechanisms of its actions.