骨质疏松症治疗新药-甲状旁腺激素的研究进展

骨质疏松症已成为严重影响老年人生活质量的慢性疾病，其发病过程复杂，危害严重，近年来的研究表明，甲状旁腺激素(PTH)是治疗骨质疏松症的理想药物。文章就PTH的基因结构、蛋白表达、生理功能及治疗骨质疏松症的进展进行了综述。     

甲状旁腺激素构效关系的研究进展

甲状旁腺激素(PTH)是生物体内调节钙、磷代谢最为重要的肽类激素之一,其氨基端1-34片段具有全分子PTH与受体结合的能力及生物活性,被广泛用于研究PTH的结构与功能。PTH二级结构中富含α-螺旋,该螺旋结构在PTH与受体相互作用中起重要作用,其中羧基端负责与受体结合,氨基端负责生理活性。现从甲状旁腺激素的结构、与受体的相互作用和构效关系等角度出发,综述了甲状旁腺激素近年来的研究状况,为开发新型骨质疏松症治疗药物提供理论依据。     

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.     

彩色多普勒超声对继发性甲状旁腺功能亢进症诊断的应用价值

目的:总结维持性血液透析患者继发甲状旁腺功能亢进症(SHP)的甲状旁腺增生的超声表现,探讨彩色多普勒超声在继发性甲状旁腺功能亢进症诊治中的应用价值。方法:对38例维持性血液透析并且血清甲状旁腺素(PTH)增高的患者进行甲状旁腺的超声检查,记录其数目、位置、大小、形态、内部回声及彩色多普勒超声表现。结果:38例患者中,36例检出增生的甲状旁腺,检出率为94.7%。共检出72枚增生的甲状旁腺,形态以椭圆形、类圆形、梭形、扁圆形为主,边界清晰,内部回声有低回声、混合回声,部分伴钙化灶,其中35枚有彩色血流。甲状旁腺的总体积及血流数与血清PTH浓度呈正相关,伴钙化灶的甲状旁腺其血清PTH浓度较高,而单个腺体最大体积与血清PTH浓度无关。结论:彩超能检测甲状旁腺的位置、数目、大小及内部回声,其总体积、内部回声及血流数与血清PTH相关,可间接反映SHP病情程度,在SHP的诊治中有重要的价值。     

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     

甲状腺乳头状癌术后甲状旁腺功能减退发生情况及严重程度的相关风险分析

目的 分析甲状腺乳头状癌术后甲状旁腺功能减退及严重程度的相关风险.方法 回顾性分析194例诊断为甲状腺乳头状癌并行甲状腺全切及中央区淋巴结清扫手术患者的临床资料.依据术后第1天的血清甲状旁腺激素(PTH)水平分为甲状旁腺功能减退组(PTH＜12 pg/mL,118例)和甲状旁腺功能正常组(PTH≥12 pg/mL,76例).分析甲状旁腺功能减退及严重程度的相关风险因素.结果 194例患者中,118例(60.8％)患者术后发生甲状旁腺功能减退.单因素分析显示,肿瘤位于后背膜、双侧中央区淋巴结清扫、淋巴结清扫数量≥10个、合并桥本甲状腺炎、术前降钙素高表达和术后引流量多与甲状腺乳头状癌术后甲状旁腺功能减退有关(P＜0.05).多因素分析结果显示,肿瘤位于后背膜和合并桥本甲状腺炎是患者术后甲状旁腺功能减退的独立危险因素(P＜0.05).118例发生甲状旁腺功能减退患者中,轻度减退35例(5 pg/mL≤PTH＜12 pg/mL),重度减退83例(0 pg/mL≤PTH＜5 pg/mL).高血压和术前血清高PTH是患者术后重度甲状旁腺功能减退的危险因素(P＜0.05).结论 甲状腺肿瘤位于后背膜和合并桥本甲状腺炎可能增加甲状腺乳头状癌患者甲状腺全切术后甲状旁腺功能减退的发生;其中,高血压及术前血清高PTH患者可能发生重度甲状旁腺功能减退.     

人血清甲状旁腺激素的测定及临床应用

人血清甲状旁腺激素(hpTH)的测定对临床某些疾病的诊断具有重要意义。本文重点介绍了hpTH的测定方法及其临床应用。应用西德MEDGENIX的hpTH放免药盒,共做56例次,其结果19例慢性肾功衰竭者PTH100％升高;26例次继发性甲状旁腺功能减退者PTH明显降低;4例次特发性甲状旁腺功能减退者PTH降低;还为3例肾结石、4例疑甲状旁腺功能减退者做了鉴别诊断。     

原发性甲状旁腺功能亢进症的临床诊断

甲状旁腺功能亢进是由于体内甲状旁腺激素（parathyroid hormone，PTH）分泌过多所致，依其发病原因不同可有原发性、继发性、三发性和异位性（假性）甲状旁腺功能亢进4种类型。原发性甲状旁腺功能亢进症（primary hyperparathyroidism，PHPT）是由甲状旁腺本身病变（肿瘤或增生）所引起。发病早期多无任何临床表现，而仅有血钙和PTH升高。是为无症状型，出现临床表现后，便属于症状型PHPT，提示病变可能已影响多数器官和系统。及时采用实验室及影像学筛查可提高PHPT的早期诊断率。综述如下。     

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。     

彩色多普勒超声检查对慢性肾衰竭患者继发性甲状旁腺功能亢进的评价

<正>慢性肾衰竭患者由于钙、磷代谢紊乱,引起低血钙及高血磷,低血钙刺激甲状旁腺主细胞增生,使内源性甲状旁腺激素(parathyroidhormone,PTH)分泌过剩,常常导致继发性甲状旁腺功能亢进(secondary hyperparathyroidism,SHP)。使甲状旁腺增生肥大,甚至形成假瘤样改变。在肾功能衰竭患者中,临床上将血清PTH≥300mg/dL定义为继发性甲状旁腺功能亢进。随着透析技术的发展,     

甲状旁腺素研究进展

甲状旁腺素是治疗骨质疏松症的重要药物,具有刺激骨骼生长,加强骨组织微结构,降低骨脆性的作用。但是,甲状旁腺素属于肽类药物需注射给药且价格昂贵,发展新型非肽类骨质疏松症治疗药物成为当前研究热点。文章综述了甲状旁腺素的生物学活性、结构特征及其构效关系,并对甲状旁腺素与受体的结合机制进行了总结,为开发新型非肽类抗骨质疏松症药物提供了理论依据。     

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.     

PTH treatment in hypoparathyroidism

Hypoparathyroidism (HypoPT) is one of the few major hormone deficiency diseases that are not usually treated with the missing hormone. Bovine parathyroid hormone (PTH) has been purified and used as experimental treatment, as long back as in 1928 by Fuller Albright. Treatment, however, was abolished mainly because of antibody formation and costs. The recent approval of fully humanized truncated parathyroid hormone (Teriparatide, PTH (1-34)) and intact parathyroid hormone (Preotact, PTH(1-84)) for treatment of osteoporosis, has made the PTH drugs more accessible and thereby made clinical trials with PTH treatment of HypoPT feasible. Resent clinical trials have shown that treatment with PTH (1-34) and PTH (1-84) can stabilize plasma calcium, normalize plasma phosphate and reduce urine excretion of calcium. Furthermore, it seems that some patients with hypoPT experience an improved quality of life when treated with PTH compared with conventional treatment with 1α-hydroxylated vitamin D metabolites and calcium supplements.     

The parathyroid hormone receptorsome and the potential for therapeutic intervention

The parathyroid hormone 1 receptor (PTH1R) is activated by parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP), hormones that mediate mineral ion homeostasis and tissue development, respectively. These diverse actions mediated by one receptor are likely due to the formation of cell-specific receptorsome complexes with cytosolic constituents. Through the second and third intracellular loops, the PTH1R couples to several G protein subclasses, including Gs, Gq/11, Gi/o and G12/13, resulting in the activation of many pathways. The PTH1R carboxy-terminal tail directs interactions with a plethora of binding partners. The WD1 and WD7 repeats of the G protein β subunit directly bind to a novel interaction domain located near the amino-terminal end of the PTH1R carboxy-terminal tail. This Gβγ binding site likely contributes to the promiscuous G protein coupling displayed by the PTH1R. Partially overlapping this site is an EF-hand binding domain that directs interactions with calpain, a calcium-activated protease, and calmodulin, a ubiquitous calcium sensor. A lysine-arginine-lysine motif located on the juxtamembrane region of the carboxy-terminal tail mediates interactions with ezrin, an actin-membrane cross-linking protein. The C-terminus of the PTH1R binds to the sodium-hydrogen regulatory factors (NHERFs) via a PDZ domain-mediated interaction, an association that influences signaling and membrane anchoring. Through direct interactions with ezrin and NHERF-1, a PTH1R receptorsome complex exists on apical membranes of the proximal tubule, an assembly that directs PTH-mediated regulation of phosphate transport. Targeting the PTH1R receptorsome will likely enhance therapies directed towards the treatment of osteoporosis and enhancing the hematopoietic stem cell niche.     

糖尿病患者高血压与趋钙激素关系的初步探讨

目的：探讨趋钙激素对糖尿病（ＤＭ）合并高血压患者发病的影响。方法：对象为４０例ＤＭ患者,其中非高血压（ＤＭ１组）２１例、合并高血压（ＤＭ２组）１９例及１５例健康对照者。对３组进行血清钙、磷、甲状旁激素（ＰＴＨ）、降钙素（ＣＴ）、葡萄糖耐量试验（ＯＧＴＴ）及胰岛素（ＩＮＳ）和Ｃ－肽（Ｃ－Ｐ）测定,并计算ＰＴＨ／ＣＴ比值和葡萄糖／胰岛素指数。结果：３组检测结果比较显示ＤＭ２组血清钙降低、ＰＴＨ升高、Ｃ     

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.     

Delivery of parathyroid hormone for the treatment of osteoporosis

Parathyroid hormone (PTH), along with its fragments and analogues, potently restores bone mass and biomechanical strength in animal models of osteoporosis, and reduces fractures by up to 65% in clinical trials in osteoporotic patients. Despite this demonstrated efficacy, patient acceptance and compliance with PTH is limited by the need for daily subcutaneous injections. The development of an equally efficacious, noninjectable form of PTH would significantly expand the present market. A challenge to the development of an alternative delivery system is the requirement for low-dose, daily, intermittent pulses of PTH to induce the anabolic actions on bone. In this review, recent basic and clinical efforts to deliver PTH by oral, buccal, sublingual, transdermal, nasal and pulmonary approaches will be addressed.     

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.     

Adverse effects of an active fragment of parathyroid hormone on rat hippocampal organotypic cultures

Adverse effects of an active fragment of parathyroid hormone (PTH(1 - 34)), a blood Ca(2+) level-regulating hormone, were examined using rat hippocampal slices in organotypic culture. Exposure of cultured slice preparations to 0.1 microM PTH(1 - 34) for 60 min resulted in a gradual increase in the intracellular Ca(2+) concentration ([Ca(2+)](i)); this effect was most obvious in the apical dendritic region of CA1 subfield. When PTH(1 - 34) at a lower concentration (1 nM) was added to the culture medium and its toxic effects examined using a propidium iodide intercalation method, significant toxicity was seen 3 days after exposure and increased with time. Cells in the CA1 region seemed more vulnerable to the hormone than cells in other regions. At 1 week of exposure, the toxic effects were dose-dependent over the range of 0.1 pM to 0.1 microM, the minimum effective dose being 10 pM. The adverse effects were not induced either by the inactive fragment, PTH(39 - 84), or by an active fragment of PTH-related peptide (PTHrP(1 - 34)), an intrinsic ligand of the brain PTH receptor. The PTH(1 - 34)-induced adverse effects were significantly inhibited by co-administration of 10 microM nifedipine, an L-type Ca(2+) channel blocker, but not by co-administration of blockers of the other types of Ca(2+) channel. The present study demonstrates that sustained high levels of PTH in the brain might cause degeneration of specific brain regions due to Ca(2+) overloading via activation of dihydropyridine-sensitive Ca(2+) channels, and suggests that PTH may be a risk factor for senile dementia. British Journal of Pharmacology (2000) 129, 21 - 28