Murray Timothy M, Rao Leticia G, Divieti Paola, Bringhurst F Richard
Department of Medicine, University of Toronto, and the Division of Endocrinology and Metabolism, St. Michael's Hospital, Toronto, Ontario, Canada.
Endocr Rev. 2005 Feb;26(1):78-113. doi: 10.1210/er.2003-0024.
PTH is a major systemic regulator of the concentrations of calcium, phosphate, and active vitamin D metabolites in blood and of cellular activity in bone. Intermittently administered PTH and amino-terminal PTH peptide fragments or analogs also augment bone mass and currently are being introduced into clinical practice as therapies for osteoporosis. The amino-terminal region of PTH is known to be both necessary and sufficient for full activity at PTH/PTHrP receptors (PTH1Rs), which mediate the classical biological actions of the hormone. It is well known that multiple carboxyl-terminal fragments of PTH are present in blood, where they comprise the major form(s) of circulating hormone, but these fragments have long been regarded as inert by-products of PTH metabolism because they neither bind to nor activate PTH1Rs. New in vitro and in vivo evidence, together with older observations extending over the past 20 yr, now points strongly to the existence of novel large carboxyl-terminal PTH fragments in blood and to receptors for these fragments that appear to mediate unique biological actions in bone. This review traces the development of this field in the context of the evolution of our understanding of the "classical" receptor for amino-terminal PTH and the now convincing evidence for these receptors for carboxyl-terminal PTH. The review summarizes current knowledge of the structure, secretion, and metabolism of PTH and its circulating fragments, details available information concerning the pharmacology and actions of carboxyl-terminal PTH receptors, and frames their likely biological and clinical significance. It seems likely that physiological parathyroid regulation of calcium and bone metabolism may involve receptors for circulating carboxy-terminal PTH ligands as well as the action of amino-terminal determinants within the PTH molecule on the classical PTH1R.
甲状旁腺激素（PTH）是血液中钙、磷和活性维生素D代谢产物浓度以及骨细胞活性的主要全身调节因子。间歇性给予PTH及氨基末端PTH肽片段或类似物也可增加骨量，目前正作为骨质疏松症的治疗方法引入临床实践。已知PTH的氨基末端区域对于PTH/PTHrP受体（PTH1R）的完全活性既是必需的也是充分的，PTH1R介导该激素的经典生物学作用。众所周知，血液中存在多种PTH的羧基末端片段，它们构成循环激素的主要形式，但长期以来这些片段一直被视为PTH代谢的无活性副产物，因为它们既不与PTH1R结合也不激活PTH1R。新的体外和体内证据，以及过去20年的早期观察结果，现在有力地表明血液中存在新型的大羧基末端PTH片段以及这些片段的受体，这些受体似乎在骨中介导独特的生物学作用。本综述在我们对氨基末端PTH“经典”受体的认识演变以及目前关于这些羧基末端PTH受体的令人信服的证据的背景下，追溯了该领域的发展。该综述总结了PTH及其循环片段的结构、分泌和代谢的当前知识，详细介绍了有关羧基末端PTH受体的药理学和作用的现有信息，并阐述了它们可能的生物学和临床意义。生理状态下甲状旁腺对钙和骨代谢的调节可能涉及循环羧基末端PTH配体的受体以及PTH分子内氨基末端决定簇对经典PTH1R的作用。
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