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Article(id=1239238139236119171, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239238136711139764, articleNumber=null, orderNo=null, doi=10.16155/j.0254-1793.2024-0226, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1712419200000, receivedDateStr=2024-04-07, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773386996324, onlineDateStr=2026-03-13, pubDate=1722355200000, pubDateStr=2024-07-31, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773386996324, onlineIssueDateStr=2026-03-13, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773386996324, creator=13701087609, updateTime=1773386996324, updator=13701087609, issue=Issue{id=1239238136711139764, tenantId=1146029695717560320, journalId=1205117023404326918, year='2024', volume='44', issue='7', pageStart='1105', pageEnd='1284', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773386995723, creator=13701087609, updateTime=1773387118529, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1239238651851370909, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239238136711139764, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1239238651851370910, tenantId=1146029695717560320, journalId=1205117023404326918, issueId=1239238136711139764, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1105, endPage=1112, ext={EN=ArticleExt(id=1239238139517137541, articleId=1239238139236119171, tenantId=1146029695717560320, journalId=1205117023404326918, language=EN, title=Research progress on the mechanism of action and bioactivity methods of human thyroid-stimulating hormone, columnId=1206272756614754650, journalTitle=Chinese Journal of Pharmaceutical Analysis, columnName=Review & Monography, runingTitle=null, highlight=null, articleAbstract=

Thyroid-stimulating hormone (TSH) is a glycoprotein hormone produced by the anterior pituitary. It can regulate the synthesis and secretion of thyroid hormone in thyroid follicular cells, which has important physiological significance. As a drug, it has important application value. Biological activity detection is an effective and necessary to evaluate its quality. This article discusses the signal transduction mechanism of thyroid stimulating hormone, the clinical diagnosis and treatment of thyroid stimulating hormone, and the determination method of biological activity.

, correspAuthors=Cheng-gang LIANG, Jing LI, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Jing GAO, Cheng-gang LIANG, Jing LI), CN=ArticleExt(id=1239238142016942755, articleId=1239238139236119171, tenantId=1146029695717560320, journalId=1205117023404326918, language=CN, title=人促甲状腺激素作用机制及生物活性方法研究进展*, columnId=1206272756753166684, journalTitle=药物分析杂志, columnName=综述专论, runingTitle=null, highlight=null, articleAbstract=

促甲状腺激素（thyroid-stimulating hormone，TSH）是由垂体前叶产生的糖蛋白激素。可调节甲状腺滤泡细胞中甲状腺激素的合成和分泌，具有重要生理学意义，作为药物具有重要应用价值，生物学活性检测是评价其质量的有效和必要手段，本文就促甲状腺激素的信号转导作用机理、促甲状腺激素的临床诊断与治疗、生物学活性测定方法进行论述。

, correspAuthors=梁成罡, 李晶, authorNote=null, correspAuthorsNote=
** 梁成罡　Tel：（010）53851638；E-mail：；
李晶　Tel：（010）53851465；E-mail：
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Tel：18261937785；E-mail：

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人促甲状腺激素作用机制及生物活性方法研究进展*
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高婧 1, 2 , 梁成罡 2, ** , 李晶 2, **
药物分析杂志 | 综述专论 2024,44(7): 1105-1112
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药物分析杂志 | 综述专论 2024, 44(7): 1105-1112
人促甲状腺激素作用机制及生物活性方法研究进展*
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高婧1, 2 , 梁成罡2, ** , 李晶2, **
作者信息
  • 1.中国药科大学 生命科学与技术学院，南京 210009
  • 2.中国食品药品检定研究院 药品监管科学全国重点实验室 国家卫生健康委员会生物技术产品检定方法及其标准化重点实验室，北京 102629

    • Tel：18261937785；E-mail：

通讯作者:

** 梁成罡　Tel：（010）53851638；E-mail：；
李晶　Tel：（010）53851465；E-mail：
Research progress on the mechanism of action and bioactivity methods of human thyroid-stimulating hormone
Jing GAO1, 2 , Cheng-gang LIANG2, ** , Jing LI2, **
Affiliations
  • 1.China Pharmaceutical University College of Life Science and Technology, Nanjing 210009, China
  • 2.National Institutes for Food and Drug Control, State Key Laboratory of Drug Regulatory Science, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, Beijing 102629, China
出版时间: 2024-07-31 doi: 10.16155/j.0254-1793.2024-0226
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摘要
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促甲状腺激素（thyroid-stimulating hormone，TSH）是由垂体前叶产生的糖蛋白激素。可调节甲状腺滤泡细胞中甲状腺激素的合成和分泌，具有重要生理学意义，作为药物具有重要应用价值，生物学活性检测是评价其质量的有效和必要手段，本文就促甲状腺激素的信号转导作用机理、促甲状腺激素的临床诊断与治疗、生物学活性测定方法进行论述。

促甲状腺激素  /  信号转导机制  /  诊断与治疗  /  骨质疏松  /  甲状腺癌  /  多囊卵巢综合征  /  生物学活性测定

Thyroid-stimulating hormone (TSH) is a glycoprotein hormone produced by the anterior pituitary. It can regulate the synthesis and secretion of thyroid hormone in thyroid follicular cells, which has important physiological significance. As a drug, it has important application value. Biological activity detection is an effective and necessary to evaluate its quality. This article discusses the signal transduction mechanism of thyroid stimulating hormone, the clinical diagnosis and treatment of thyroid stimulating hormone, and the determination method of biological activity.

thyroid-stimulating hormone  /  signal transduction mechanism  /  diagnosis and treatment  /  osteoporosis  /  thyroid cancer  /  polycystic ovary syndrome  /  biological activity assay
高婧, 梁成罡, 李晶. 人促甲状腺激素作用机制及生物活性方法研究进展*. 药物分析杂志, 2024 , 44 (7) : 1105 -1112 . DOI: 10.16155/j.0254-1793.2024-0226
Jing GAO, Cheng-gang LIANG, Jing LI. Research progress on the mechanism of action and bioactivity methods of human thyroid-stimulating hormone[J]. Chinese Journal of Pharmaceutical Analysis, 2024 , 44 (7) : 1105 -1112 . DOI: 10.16155/j.0254-1793.2024-0226
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促甲状腺激素(thyroid-stimulating hormone，TSH)是由垂体前叶产生的糖蛋白激素，是一种异源二聚体糖蛋白，相对分子质量为2.8×104~3.0×104，由1个α-亚基(92个氨基酸)和1个β-亚基(112个氨基酸)组成。α-亚基是TSH、促黄体激素(LH)、促卵泡激素(FSH)和胎盘绒毛膜促性腺激素(CG)共同存在的，而β-亚基是每一种激素所特有的，赋予分子自身的生物活性[1]。
TSH的合成离不开下丘脑-垂体-甲状腺轴(hypothalamic-pituitary-thyroid axis)的作用，如图1所示，下丘脑合成促甲状腺激素释放激素(thyrotropin-releasing hormone，TRH)，垂体合成TSH，甲状腺合成甲状腺激素(thyroid hormone)。进一步来说，位于下丘脑室旁核(paraventricular nucleus，PVN)的神经元可合成TRH。虽然含TRH的神经元广泛分布于整个大脑，但PVN中的TRH神经元均匀分布于正中隆起，这是一个通过下丘脑-垂体-门脉血管连接到垂体前叶的神经血管器官，是唯一调节垂体-甲状腺轴的TRH神经元[3]，且只有PVN受到甲状腺激素的严格调控。甲状腺激素结合PVN中的甲状腺激素受体β2亚型，对TRH基因表达进行负反馈调节。垂体门静脉系统将TRH输送到垂体前叶，在那里合成和分泌TSH[4]。TSH的唯一生物学功能是调节甲状腺滤泡细胞中甲状腺激素的合成和分泌，即调节甲状腺滤泡细胞中三碘甲状腺原氨酸(triiodothyronine，T3)和甲状腺素(thyroxine，T4)的释放。大约80%的甲状腺激素以T4的形式释放，T4可脱碘成为T3，T4和T3在这一步也会产生负反馈调节，高水平的T3/T4减少垂体前叶的TSH释放，而低水平的T3/T4增加TSH释放[5]。
1　TSH的信号转导作用机理
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TSH主要通过与位于甲状腺滤泡细胞表面的同源受体促甲状腺激素受体(TSH receptor，TSHR)结合发挥作用。TSHR是一种细胞表面糖蛋白受体，属于G蛋白偶联七跨膜受体的富含亮氨酸重复序列(LGR)亚家族。如图2-B所示，TSHR由细胞外结构域——富含铰链和亮氨酸的重复结构域(leucine-rich repeat domain，LRRD)、跨膜结构域和细胞质内结构域3个部分组成。其中2个半胱氨酸形成二硫键。TSHR基因的基因组结构如图2-A所示，TSHR基因共有10个外显子。前9个外显子从氨基末端开始构成胞外结构域(胞外区)，而第10个外显子则编码7个跨膜片段以及1个包含细胞质内结构域的羧基末端区域[6]位于甲状腺细胞中的大多数TSHR经过翻译后修饰过程，在铰链区的2个位点被蛋白水解酶酶切，使LRRD-铰链区之间或铰链区内部的二硫键脱落，经过脱落和切割的共同作用，最终从“受体亚基B”(N末端的C末端部分和蛇形结构域)释放出所谓的“受体亚单位A”(由LRRD和部分铰链区组成)，切割加脱落是GPHR组中TSHR所独有的。酶切掉的部分为含有50个氨基酸的铰链区(也称为C肽)。TSHR还经历了N-连接的糖基化、棕榈酰化和唾液酸化、二聚化等翻译后修饰过程，这些修饰影响受体的细胞表面表达或信号转导，以实现完整的功能。细胞外A亚基具有TSH结合位点，由富含亮氨酸的LRRD组成。与TSH或β-抑制蛋白、G-蛋白偶联受体激酶和RGS蛋白结合后的构象变化导致TSHR的激活，从而打开细胞内B亚基偶联的下游信号通路，即G蛋白偶联的系列反应[7]。
TSH发挥作用的第1步是TSH与TSHR结合，激活2种Gα蛋白亚型：Gs和Gq。这些蛋白质分别激活2种不同的调节途径：cAMP途径和磷脂酶C(PLC)途径。如图3所示，①cAMP途径：2a.Gs激活腺苷酸环化酶；3a.AC将三磷酸腺苷(ATP)转化为cAMP；4a.cAMP与蛋白激酶A(PKA)的调节亚基(R)结合，释放并激活该蛋白的催化亚基(C)；5a.激活的PKA激活参与甲状腺激素产生的基因的转录，包括碘化钠转运体(sodium iodide symporter，NIS)、甲状腺球蛋白(thyroglobulin，TG)和甲状腺过氧化物酶(thyroid peroxidase，TPO)。②PLC途径：(2b)Gq激活PLC将磷脂酰肌醇4，5-二磷酸(PIP2)水解为二酰甘油(DAG)和肌醇1，4，5-三磷酸(IP3)；(3b)IP3与其内质网受体结合，释放储存在该细胞器中的Ca2+；(4b)细胞内Ca2+增加，过量的Ca2+会释放到细胞外，同时激活钙调素依赖性蛋白激酶(CaMK)；(5b)DAG激活蛋白激酶C(PKC)；(6b)通过CaMK和PKC的激活，调节碘化物顶端流出、H2O2的产生、甲状腺球蛋白碘化和一氧化氮合酶的组成型激活[8]。
综上，TSH是与甲状腺功能调节有关的主要生理激素。TSH通过激活TSHR作用于滤泡甲状腺细胞，介导cAMP和PLC 2种级联调节途径的激活。一方面，可以通过cAMP-PKA途径调节碘摄取和甲状腺激素产生相关基因的转录：碘化钠转运体、甲状腺球蛋白和甲状腺过氧化物酶。另一方面，通过PLC-PIP2-IP3-Ca2+-CaMK调节碘化物(I-)顶端流出，流出的I-主要通过pendrin通道输送到胶体中，参与甲状腺激素的合成；通过双氧化酶2(dual oxidase 2，DUOX-2)激活产生H2O2、甲状腺球蛋白碘化和一氧化氮合酶的组成型激活；或者通过PLC-PIP2-DAG激活蛋白激酶C，进而激活蛋白激酶D，增强碘化作用，并激活参与甲状腺激素产生的基因的转录，如DUOX-2。为甲状腺激素的合成提供所需要的酶和前体[10-11]。甲状腺激素的合成过程如图4所示，具体步骤包括：1.碘摄取；2.甲状腺球蛋白分泌；3.碘化；4.T4合成；5.内吞作用；6.蛋白质水解；7.游离的T4和T3。
2　TSH的临床诊断与治疗
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2.1　TSH的临床诊断作用
TSH是由垂体分泌的激素。这个过程一方面受下丘脑分泌的TRH的促进性影响，另一方面又受到甲状腺激素反馈性的抑制性影响，二者互相拮抗，它们组成下丘脑-垂体-甲状腺轴。TSH偏低时，说明体内甲状腺激素分泌过多，从而抑制TSH的合成，所以原发性甲状腺功能亢进症会导致TSH水平降低，与此相关的甲状腺疾病还包括继发性甲状腺功能减退症，甲状腺癌等；而对于原发性甲状腺功能减退症的患者来说，血液中的T3、T4会呈现出不同程度的下降，垂体所分泌的TSH就会随之升高，TSH水平升高还与TSH分泌瘤、甲状腺激素抵抗综合征等疾病有关。测定血清(浆)中的TSH是诊断和治疗甲状腺功能亢进症和甲状腺功能减低症以及研究下丘脑-垂体-甲状腺轴的重要指标之一。在诊断甲状腺功能低下和鉴别诊断原发性和继发(下丘脑性或垂体性)甲状腺功能低下等方面是不可缺少的工具[12]。
TSH水平与甲状腺功能息息相关，通过比较分化型甲状腺癌患者、甲状腺良性结节患者及健康人群中血清TSH、甲状腺球蛋白及抗甲状腺球蛋白抗体3项指标水平，确定这3项指标可以作为分化型甲状腺癌患者病情诊断的重要参考依据[13]。通过比较甲减患者与健康人群中血清游离三碘甲腺原氨酸(free triiodothyronine，FT3)、游离甲状腺素(free thyroxine，FT4)、TSH及同型半胱氨酸(homocysteine，Hcy)4项水平的高低，发现甲减患者的血清FT3和FT4水平明显降低，血清TSH和Hcy水平明显升高。得到可采用FT3、FT4、TSH及Hcy联合检查的方法对甲状腺功能减退进行诊断的结论[14]。也有研究通过比较桥本甲状腺炎患者、甲状腺机能减退症患者、毒性弥漫性甲状腺肿患者与正常人的血清TSH、抗甲状腺过氧化酶抗体、抗甲状腺球蛋白抗体及TSHR抗体水平，发现检测TSH水平有利于诊断甲状腺功能特异性，检测抗甲状腺过氧化酶抗体与抗甲状腺球蛋白抗体水平可诊断自身免疫性甲状腺疾病，检测TSHR抗体水平可用于诊断毒性弥漫性甲状腺肿[15]。
TSH是甲状腺功能变化最敏感的指标，甲状腺功能障碍可增加心血管疾病的风险[16]。在临床上，有研究发现TSH浓度与血压升高呈正相关[17]。有研究指出，TSH在0.5-3.5 mU·L-1的参考值范围内，与收缩压和舒张压呈线性正相关，表明TSH浓度可能对心血管状况有长期影响[18]。研究表明，血清TSH水平与致动脉粥样硬化的脂质谱呈正相关，TSH可能控制脂质稳态，从而可能调节心血管疾病[19]。TSH水平似乎与颈动脉内膜-中膜厚度(CIMT)密切相关，这是早期动脉粥样硬化变化的标志[20]。
2.2　TSH相关疾病及治疗
TSH的生理功能是促进甲状腺滤泡发育和激素分泌。与甲状腺机能亢进相关的骨质疏松症传统上被认为是甲状腺功能改变的继发性后果[21]。有研究指出TSH与骨骼重塑有关。在大鼠骨质疏松模型中，TSH在剂量水平低于引起甲状腺反应所需剂量时，对骨强度和质量有积极影响。TSH具有控制骨形成和骨吸收的作用。可能成为晚期骨质疏松症治疗的一个有希望的候选药物[22]。
手术治疗甲状腺癌后会出现甲状腺功能减退等并发症，TSH可用于术后辅助治疗，以改善患者的生化和内分泌指标。有研究对术后服用左旋甲状腺素钠片的剂量设置常规剂量的对照组和抑制剂量的观察组进行比较，TSH能促进机体产生甲状腺激素，并且给予TSH抑制剂量治疗，不仅改善甲状腺功能而且能够帮助患者将体内的TSH分泌抑制在一定水平，以防再次出现肿瘤细胞[23]。
多囊卵巢综合征临床生化表现为雄激素分泌增加、排卵水平降低或无排卵、胰岛素抵抗等，且可见卵巢多囊性改变，并发症为高血脂、冠心病、糖尿病等[24]。药物是控制该病的主要手段，二甲双胍属于降糖药，是临床治疗多囊卵巢综合征的常用药物，但单一用药效果不佳[25]。TSH可与卵巢颗粒细胞上的TSHR结合，激活环磷酸腺苷、腺苷酸环化酶，从而促进卵泡成熟，而且甲状腺功能障碍与胰岛素抵抗发生相关，会降低糖脂代谢能力，引起经期紊乱，影响女性生殖系统功能，进而对女性排卵情况造成影响[26]。有研究以多囊卵巢综合征患者作为研究对象，分为采用二甲双胍治疗的参照组，和采用二甲双胍联合TSH治疗的研究组，比较2组患者治疗前后生殖激素指标及糖脂代谢指标变化情况。结果表明采用TSH治疗多囊卵巢综合征患者，能明显提高糖脂代谢能力，改善患者生殖分泌功能[27]。
3　生物学活性测定方法
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生物学活性是反映生物制品药物有效性的关键质量属性，因此TSH生物学活性检测是评价其质量的必要手段。下面介绍几种检测方法。
3.1　基于动物实验的活性检测方法
1958年，Mckenzie[28]以甲状腺对I131的摄取为基础，给小鼠注射I131，然后通过给予甲状腺素抑制内源性TSH，然后静脉注射TSH，通过血液中I131的百分比增加来指征TSH的活性。该方法也是最早的体内TSH检测方法之一。1984年，Bidey等[29]用放射免疫分析法(RIA)检测了TSH治疗后，FRTL-5细胞中cAMP水平的升高来测定TSH的活性。1990年，Thotakura等[30]通过TSH在牛甲状腺膜匀浆中刺激cAMP产生的能力用于量化TSH活性。结果表明，去糖基化会导致牛TSH活性降低。同年，Yuichi等[31]利用单克隆抗体对人TSH生物学活性的抑制作用可减少基础cAMP的积累的原理，对胸腺嘧啶氚化，用液体闪烁计数器对放射性进行计数的方法表征FRTL-5细胞中(3H)胸苷摄取的情况，得出了β亚基上不同表位的单克隆抗体完全抑制了人TSH与FRTL-5大鼠甲状腺细胞的受体结合，而针对α亚单位上不同表位的5种单克隆抗体对受体结合几乎没有影响的结论。由于动物实验周期长，个体差异性大，操作熟练度要求高，变异性大，活性变化敏感度低等弊端，不符合“3R”原则，大力开发动物实验替代方法已成为共识。
3.2　体外生物学活性检测方法
2019年，Van等[32]提出了一种基于膜的微波介导的检测TSH抗原的方法，采用夹心ELISA的形式用于高响应性电化学免疫分析，该免疫分析法具有低成本，敏感、特异、快速和即时诊断TSH的优点。但是该方法只能以免疫反应测得具有免疫活性的物质，其实质是基于蛋白序列抗原表位的含量测定方法，不能区分所测得的分子是否具有生物学功能，因此测定结果与生物测定结果可能不一致。2022年，Liu等[33]开发了一种基于NaYF4∶Yb，Er之间发光共振能量转移(LRET)的简单免洗生物适体传感器，在这个LRET系统中，转换纳米颗粒(UCNPs)作为供体，四基罗丹明(TAMRA)作为受体，分别用核酸适配体Apt-1和Apt-2修饰。当TSH存在时，2个适配体链都能特异性识别TSH，形成发夹状结构，从而缩短UCNPs和TAMRA之间的距离。在980 nm光的照射下发生LRET。通过检测上转换发光(UCL)强度(I545 nm)的变化来定量TSH的活性。该检测方法灵敏度高，制备简单，操作方便，选择性好，能够有效消除复杂生物环境的背景干扰，尽管RNA适体不如DNA稳定，但RNA更灵活，有助于与小分子的强识别相互作用，从而提高选择性。该适体传感器在未来的临床TSH检测和分析应用中显示出了其潜力。然而，还需要进一步研究非特异性吸附的干扰，并将临床样本的检测结果与多种技术的检测结果进行比较，以形成统一的定量指标，但其本质仍然是含量测定方法。这2种方法都没有利用TSH与受体结合后诱导产生的一系列反应，不能模拟体内药效，不能真实反映TSH的生物学活性。所以，开发以细胞为基础的体外生物学活性检测方法意义重大，通过信号通路的作用，模拟药物在人体中发挥作用的方式，对生物学活性有直观的反映。
使用基于细胞的体外方法替代动物测定是国内外生物技术产品质控的发展趋势。用于TSH活性测定的细胞方法也有一些报道。1996年，Hussain等[34]构建了转染TSHR和CRE-Luc中国仓鼠卵巢(CHO)细胞，利用TSH与受体结合后导致细胞内荧光素酶的增加量与TSH水平成正比的原理，对人TSH和重组人TSH的生物学活性进行了比较，表明2种TSH具有同等效力。近期，国内已经批准上市的重组人TSH生物学活性测定方法为酶联免疫法和均相时间分辨荧光法。原理都是利用不同重组人TSH的浓度下，细胞内产生的环磷酸腺苷的含量不同，通过检测cAMP的含量反映重组人TSH的生物学活性。ELISA是利用双抗夹心法测定TSHR-HEK 293细胞内产生的cAMP的含量，HTRF法则是测定TSHR-CHO-E7细胞株中cAMP的含量，2种方法都是利用稳定表达人TSHR基因的细胞株。2种方法高效快速，具有良好的准确性、可靠性、重现性。
综上，利用TSH与TSHR结合之后激活cAMP途径这一原理检测TSH体外生物学活性是主要方法，靶细胞为原代的甲状腺滤泡细胞，但由于原代细胞分离和培养的成本较高，生长缓慢，不易培养等缺点，转向永生化细胞是一个趋势，需要向细胞中导入TSHR，然后通过(1)cAMP途径，激活与TSHR偶联的Gαs蛋白，产生cAMP，磷酸化的CREB通过识别其位于基因启动子区的特异性反应元件CRE改变下游基因的转录。也可通过(2)PLC途径，激活与TSHR偶联的Gαq蛋白，继而导致PLCβ-IP3-Ca2+通路的激活，Ca2+的上调也引发了NFAT蛋白快速易位至细胞核中，通过识别其位于基因启动子区的特异性反应元件NFAT-RE改变下游基因的转录，如图5所示，可通过报告基因法检测，通过检测下游信号强度表征生物学活性。而且上述2条途径是与TSH功能密切相关的信号转导途径，其调控的基因负责调节碘的摄取或者参与甲状腺激素的产生，包括钠碘转运体、甲状腺球蛋白和甲状腺过氧化物酶。这种以细胞为基础的体外生物学活性检测，利用药物作用信号通路，不仅可以对活细胞功能进行研究，而且更加贴近生理状态，更能直观地、针对性地反映药物的靶向作用，具有灵敏度高，操作简便，可靠性好，高效快速的优点。
4　展望
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TSH能够促进甲状腺的生长以及促进甲状腺功能的发育，具有重要生理意义。血清中的含量也成为临床检测甲状腺患者病症的重要检测指标。TSH对骨质疏松症、甲状腺癌、多囊卵巢综合征等疾病都有疗效，也与心血管疾病相关，未来对TSH分子功能域进行修饰或开发安全有效的TSH类似物具有重要研究价值。作为药物在临床上具有重要的诊断和治疗价值，生物学活性检测是评价其质量的有效和必要手段，因此开发简单、有效、快速的体外生物学活性检测方法具有重要意义。TSH与TSHR结合后可促进甲状腺球蛋白的表达，可作为报告基因法检测TSHR生物学活性检测的新思路。
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  • * 药品监管科学全国重点实验室(2023SKLDRS0108)
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doi: 10.16155/j.0254-1793.2024-0226
  • 接收时间：2024-04-07
  • 首发时间：2026-03-13
  • 出版时间：2024-07-31
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    1.中国药科大学 生命科学与技术学院，南京 210009
    2.中国食品药品检定研究院 药品监管科学全国重点实验室 国家卫生健康委员会生物技术产品检定方法及其标准化重点实验室，北京 102629

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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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