甲状旁腺激素相关肽与骨质疏松

甲状旁腺激素相关肽（PTHrP,1-36)是体内一种真实的分泌形式,它与甲状旁腺激素（PTH,1－34）具有很高的同源性,不仅一级序列同源,三级结构相似,而且能与共同的受体PTH／PTHrP受体相结合,在实验动物和人体上均有效地促进骨骼合成。本文从理论上解释了PTHrP(1-36)作为骨质疏松潜在药物的可能性。     

治疗骨质疏松症药物研究进展（二）

2 骨形成促进药物 2．1 人重组甲状旁腺素1-34（Recombinant Human Parathyroid Hormone，rhPTH 1-34）：人体天然甲状旁腺素（Parathyroid Hormone，PTH）含有84个氨基酸。人重组甲状旁腺素1-34具有与人体天然甲状旁腺素N端34个氨基酸序列完全相同的结构．其生物学作用亦是通过与特异性高亲和性人体天然甲状旁腺素-I受体结合介导的。人重组甲状旁腺素1-34于2002年已获FDA批准上市，商品名为Forteo，是目前唯一促进骨形成的药物，     

慢性肾功能衰竭与继发性甲状旁腺功能亢进症关系研究新进展

本文概述了慢性肾功能衰竭(chron ic renal failure,CRF)与继发性甲状旁腺功能亢进症(secondary hyperparathyroid-ism,SHPT)的关系在近几年的进展,从甲状旁腺激素(para-thyroid hormone PTH)的生理病理、磷的作用、钙敏感受体及激动剂、活性维生素D及其受体以及PTH的基因表达等方面,探讨其发病机制,旨在为临床提供新思路。     

慢性肾功能衰竭血透患者甲状旁腺激素(PTH)升高程度对残余肾功能的影响

目的:研究与分析慢性肾功能衰竭血透患者甲状旁腺激素(PTH)升高程度对残余肾功能的影响。方法:选取在2017年1月-2018年3月时间内来我院进行治疗的患有慢性肾功能衰竭的患者67例,随后采取甲状旁腺激素升高程度将这67例患者分为低甲状旁腺激素组(33例,PTH500 ng/L)与高甲状旁腺激素组(34例,PTH500ng/L)。两组患者均进行血液透析治疗,随后检测患者的肾功能情况。结果:高甲状旁腺激素组与低甲状旁腺激素组患者的血尿素氮、血肌酐以及内生肌酐清除率等变化幅度差异显著,前者显著高于后者,数据对比具有统计学意义(t值=2.6321,3.0953,5.9611,p0.05)。结论:慢性肾功能衰竭患者进行血透的过程中往往会出现甲状旁腺激素的情况,且升高幅度越大,其对残余肾功能的损害程度越大。     

重组人甲状旁腺激素基因工程研究进展

甲状旁腺激素（parathyroid hormone,PTH）是由甲状旁腺主细胞分泌的碱性单链多肽类激素。它主要调节脊椎动物体内钙和磷的代谢。目前,PTH及其类似物已成为治疗骨质疏松症的首选药物。随着PTH基因序列的阐明,通过基因工程手段获得高效、低毒、稳定的重组PTH,已成为研究热点。本文对PTH的结构功能、基因工程研究及临床应用问题进行综述。     

高血压与甲状旁腺激素

大量研究以及实验模型显示钙的动态平衡与心血管风险的增加有关,特别是钙系统代谢的改变被认为对血压是重要的调节因素,有人认为这种关系可能与甲状旁腺激素（parathyroid hormone,PTH）水平有关.在原发性甲状旁腺亢进中,PTH的自主分泌导致了高钙血症.已有研究表明,PTH水平与高血压有正相关.同时在一些研究中也发现,有高血压的病人相比于正常人有更高的PTH水平.这些数据让人猜测PTH可能与高血压的发病机制有关.     

治疗骨质疏松的微电子贴剂结果肯定

以色列的透皮药物输送公司Trans-pharma Medical报告了其输送人甲状旁腺激素hPTH（1—34）的透皮贴剂治疗骨质疏松症的肯定结果。hPTH（1-34）是负责调节人体内钙和磷代谢的PTH肽片段，具有与天然存在的内源激素hPTH（1-84）相同的生物活性。     

钙代谢调节剂骨化三醇治疗继发性甲状旁腺机能亢进

肾功衰竭继发甲状旁腺机能亢进的治疗还有待研究。维生素D或其活性代谢产物可增加血清钙浓度,促进肠道钙吸收。近来,人们已公认1,25-(OH)_2VD_3(骨化三醇)对甲状旁腺功能有重要作用。甲状旁腺组织含有骨化三醇受体,骨化三醇可抑制甲状旁腺激素(PTH)基因表达及甲状旁腺细胞增殖。作者研究21例晚期肾衰患者,年龄3～21岁,其中血液透析(HD)者7例,不卧床持续腹膜透析(CAPD)者14例。骨化三醇治疗剂量为每天口服0.25～1μg。PTH浓度(正常1～6 pmol/L)轻度增高至50 pmol/L     

甲状旁腺素和甲状旁腺素相关肽在皮肤病中的研究进展

甲状旁腺素（ PTH）和甲状旁腺素相关肽（ PTHrP）是一类多肽类激素,它们具有相似的基因结构、相同的膜受体,在人体钙、磷代谢过程中起着重要的调节作用。 PTH和PTHrP及其受体除表达于肿瘤组织外,在皮肤、毛囊等正常组织也有表达。它们对表皮增殖分化、毛发生长的生理作用等方面,有望成为银屑病等常见皮肤病的治疗新靶点。     

甲状旁腺激素对心脏作用的研究近况

<正> 甲状旁腺激素(PTH)是体内重要的调钙激素,骨骼、肾脏是其重要的靶器官,它们在调节血钙、维持其平衡中起着重要作用。近年来一些研究表明,PTH还作用于骨、肾以外的其它器官,如肝、脑、血细胞、神经系统、心血管系统等。本文仅就PTH对心脏的作用做一简单综述。     

甲状旁腺激素生理作用和构效关系研究

对甲状旁腺激素的生理作用及机制、分子结构、受体结合和构效关系等方面的研究作一综述，以期为开发新型骨质疏松症治疗药物提供理论依据。甲状旁腺激素是一种生理活性多肽，体内独特的成骨作用使其作为治疗骨质疏松症药物的研究日益深入。     

Developments in parathyroid hormone and related peptides as bone-formation agents

Osteoporosis is a major and growing healthcare concern. When administered by daily injection, parathyroid hormone (PTH) and its N-terminal fragments and analogs are potent bone-formation agents. Teriparatide, recombinant human PTH(1-34), is likely to be the first anabolic agent approved for treating osteoporosis, despite inducing osteosarcomas in rats. Native PTH and other PTH fragments and analogs are also in development. N-terminal fragments sometimes differ in activity from the native hormone, however, and the C-terminal region of PTH, acting through a receptor different from the classical PTH-1 receptor, initiates a variety of distinct biological activities. In particular, the C-terminal region of PTH, by promoting bone-cell apoptosis, may be important in opposing the anti-apoptotic effects of teriparatide in these cells, thereby maintaining normal bone-cell turnover. Because of these differences, care must be taken to consider the effects of native PTH and N-terminal PTH fragments and analogs separately.     

Molecular mechanisms of ligand recognition by parathyroid hormone 1 (PTH1) and PTH2 receptors

The mammalian parathyroid hormone (PTH) / PTH receptor family includes PTH1 and PTH2 receptors and three related ligands (PTH, PTH-related protein (PTHrP) an d tuberoinfundibular peptide of 39 residues (TIP39)). Here we comparatively and systematically review the pharmacological properties of PTH receptors and ligands, structure of the ligands, and molecular mechanisms of receptor-ligand interaction. The PTH1 receptor is activated by PTH and PTHrP but not by TIP39. The PTH2 receptor is activated by TIP39 but not by PTHrP. PTH strongly activates the human PTH2 receptor but is a weak partial agonist for rat and zebrafish PTH2 receptors. Receptor-G-protein interaction increases the receptor binding selectivity of PTHrP and TIP39. Despite different primary structures, the secondary structures of PTH, PTHrP and TIP39 are quite similar. Each ligand contains an N-terminal and a C-terminal alpha-helix in secondary structure-inducing conditions. Receptor-bound ligand structure is less well-characterized. The orientation of receptor-ligand interaction is highly similar for PTH and PTHrP binding to the PTH1 receptor and TIP39 interaction with the PTH2 receptor. Ligands bind according to a 'two-site' mechanism, in which the C-terminal portion of the ligand binds the extracellular N-terminal domain of the receptor (N-interaction), and the N-terminal ligand portion binds to the juxtamembrane receptor domain (J-interaction). The N-interaction provides most of the PTH1-receptor binding energy for PTH and PTHrP but provides less energy for PTH2 receptor-TIP39 interaction. The J-interaction stimulates G-protein activation. For the PTH-PTH1 receptor interaction, the efficacy-generating component of the J-interaction is independent of the N-domain of the receptor and C-terminal portion of the ligand. This finding suggests that it might be possible to design low molecular-weight PTH1 receptor agonists, which could be bone anabolic agents and used for the treatment of osteoporosis.     

Synthesis and structural identification of fluorine‐18 labeled parathyroid hormone

Parathyroid hormone (PTH) is an 84 amino acid peptide hormone that plays a key role in bone and mineral metabolism. The biological actions of PTH are mediated via the N‐terminal PTH(1–34) fragment, serving as the PTH receptor‐binding sequence, and which is therefore used clinically to treat conditions of low bone mass such as osteoporosis. In this study, PTH(1–34) was conjugated with non‐radioactive (stable F isotope) N‐succinimidyl 4‐fluorobenzoate (SFB) leading to three isomeric mono‐fluorobenzoated (FBz) PTH followed by Liquid chromatography‐Tandem mass spectrometry (LC‐MS/MS) assisted structural identification. Corresponding [¹⁸F]SFB‐labeled PTH derivatives were prepared respectively and the Lys¹³ site‐specific labeled [¹⁸F]FBz PTH was isolated by HPLC with radiochemical purity >99% and specific activity of 2.78 GBq/µmol, suitable for future application with in vivo pharmacokinetic/pharmacodynamic studies of PTH, using preclinical Positron Emission Tomography Computed Tomography (PET/CT) imaging.     

Parathyroid hormone (1-34): a major advance in the treatment of osteoporosis?

Osteoporosis is a major public health problem for older women and men. Parathyroid hormone (PTH) (1-34), which produces similar biological activity to the parent hormone, was tested in postmenopausal women with prior vertebral fractures. In 18 months, PTH (1-34) caused a dramatic 65% decrease in the risk of new vertebral fractures with a 10% increase in bone mineral density with few side effects. PTH (1-34) represents an exciting new therapy for this high risk group.     

Parathyroid hormone and parathyroid hormone-related protein: model systems for the development of an osteoporosis therapy

The parathyroid hormone (PTH) plays a vital role in the homeostasis of calcium within the blood stream. Given its unique ability to increase bone density, an understanding of the molecular mechanism by which the hormone is recognized and binds to its receptor should provide targets for the development of PTH-based, anabolic agents for the treatment of osteoporosis. Parathyroid hormone related protein (PTHrP), a genetically and structurally distinct hormone which displays similar binding and activation profiles as PTH, has greatly facilitated the effort to establish a structure-biological function relationship by allowing for direct comparisons. In an analogous manner, the presence of two receptors, PTH/PTHrP (PTH1) and PTH2, which differ in their ligand selectivity (PTH2 is activated by PTH, not PTHrP) has provided a unique vehicle for probing the structural motifs of the receptor required for ligand recognition and binding. Recent photo-affinity cross-linking studies of PTH and PTHrP binding to PTH1 have produced direct points of contact between the ligand and receptor. Here, we review each of the components involved in this important hormone system, with particular emphasis on the structural features of each: the ligands (PTH and PTHrP), the receptors (PTH1 and PTH2), and the interaction between ligand and receptor. Although the current understanding of the molecular mechanism of ligand binding and receptor activation does not allow for the rational design of drug candidates, and indeed contains much conjecture, significant strides have been made towards this end.     

3‐(3′‐Fluorenyl‐9′‐oxo)‐l‐alanine: a novel photoreactive conformationally constrained amino acid

Abstract: Photoaffinity scanning of the ligand–G‐protein‐coupled receptor bimolecular interface is a direct approach to mapping the interactions of ligands and receptors. Such studies are an important first step toward generating an experimentally based model of the ligand–receptor complex. The synthesis and spectroscopic characterization of Boc‐3‐(3′‐fluorenyl‐9′‐oxo)‐l ‐alanine and 9‐fluorenone‐3‐carboxylic acid are described. Incorporation of these two photophores into the parathyroid hormone (PTH) molecule yields potent agonists. These photoreactive analogs cross‐link specifically with the recombinant human PTH1 receptor stably expressed in human embryonic kidney cells. The availability of the 9‐fluorenone (a conformationally constrained derivative of benzophenone, the abundantly used photophore) for photoaffinity scanning provides an important tool to probe the effect of conformational flexibility of the photophore on the selection of the cross‐linking site in the macromolecular acceptor.     

Non-canonical signaling of the PTH receptor

The classical model of arrestin-mediated desensitization of cell-surface G-protein-coupled receptors (GPCRs) is thought to be universal. However, this paradigm is incompatible with recent reports that the parathyroid hormone (PTH) receptor (PTHR), a crucial GPCR for bone and mineral ion metabolism, sustains G(S) activity and continues to generate cAMP for prolonged periods after ligand washout; during these periods the receptor is observed mainly in endosomes, associated with the bound ligand, G(S) and β-arrestins. In this review we discuss possible molecular mechanisms underlying sustained signaling by the PTHR, including modes of signal generation and attenuation within endosomes, as well as the biological relevance of such non-canonical signaling.     

人甲状旁腺激素(1-34)突变蛋白的设计与活性验证

通过对NCBI数据库中不同物种同源序列进行比对protein-protein BLAST,并利用计算机软件DiscoveryStudio3.1进行分子对接和分子动力学模拟,对天然人甲状旁腺激素(1 34)的3个氨基酸R25K26K27进行Q25E26L27置换,并对突变体的生物活性进行了评价。结果显示:突变后PTH(1 34)-(RKK-QEL)和突变前PTH(1 34)多肽主链叠合后均方根偏差RMSD值为2.509 3,说明两者主链结构构象差异不大;PTH(1 34)-(RKK-QEL)与受体蛋白PTH1R的相互作用能为599.253 kcal.mol 1,较天然PTH(1 34)的554.083 kcal.mol 1增强7.5%;氢键数目由32对增加至38对;PTH(1 34)-(RKK-QEL)能显著刺激UAMS-32P细胞RANKL基因的表达(P<0.01),并抑制OPG基因的表达(P<0.01);PTH(1 34)-(RKK-QEL)作用于UAMS-32P和小鼠原代股骨骨髓细胞共培养体系时,能显著刺激破骨细胞的形成(P<0.01),并且活性高于PTH(1 34)标准品。     

Constrained analogs of osteogenic peptides

Osteogenic peptides are, or have potential to be, therapies for the treatment of osteoporosis, fracture repair, and repair of loosened bone implants. Human parathyroid hormone has been approved for the treatment of post-menopausal osteoporosis. Constrained analogs of PTH and the parathyroid-hormone related peptide (PTHrP) have aided the understanding of how PTH and PTHrP bind to their common receptor and some of these analogs have improved properties that make them possible candidates for clinical trial. Cyclization by lactam formation has shown that a core region of human PTH (hPTH) from residues 16-26 binds as an alpha-helix to the receptor and that the biological effects are remarkably sensitive to ring size. Appropriate cyclization in this region of the molecule not only has yielded analogs with improved receptor activation but also ones less susceptible to protease degradation and thus more active in vivo. Cyclization has been less successful in the N-terminus region, residues 1-12, of hPTH(1-34) with only a cyclization between residues 6 and 10 showing some promise. The growing understanding of how this region binds to the receptor will lead to other productive constraints. This review also covers the potential of a different class of molecule, the osteogenic growth peptide (OPG), as an anabolic bone agent. These molecules have much weaker anabolic effects than PTH and cyclization does not result in improved activity. However, the information gained from these studies may yield analogs with better pharmacological profiles.