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Song X, Zhi X, Qian L. Tailoring TSH suppression in differentiated thyroid carcinoma: evidence, controversies, and future directions. Endocrine 2025:10.1007/s12020-025-04223-w. [PMID: 40199841 DOI: 10.1007/s12020-025-04223-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2025] [Accepted: 03/24/2025] [Indexed: 04/10/2025]
Abstract
PURPOSE This review focus on the controversial benefits of thyroid hormone suppression therapy (THST) in differentiated thyroid carcinoma (DTC) and its associated risks, highlighting the need for individualized strategies to optimize therapeutic outcomes and guide future research. METHODS A systematic literature search on TSH suppression in DTC over the past 10 years was conducted, prioritizing RCTs, large cohort studies, and non-inferiority trials, with additional references identified from retrieved articles. RESULTS Tailored postoperative TSH strategies should consider factors such as risk stratification, treatment modality, histologic subtype, and adverse effect risks. In this context, mechanistic studies offer potential insights that could inform personalized TSH management, though further validation is required. Clinical evidence on THST in DTC remains controversial, particularly for high-risk patients, where support for stringent TSH suppression (<0.1 mU/L) is limited. Data for intermediate-risk DTC are insufficient due to cohort heterogeneity, while TSH suppression in low-risk DTC is largely discouraged. The well-documented adverse effects of excessive THST, including cardiovascular complications and osteoporosis, further provide a strong rationale against its routine use. Additionally, achieving and maintaining target TSH levels in real-world practice remains challenging, underscoring the need for refined approaches. CONCLUSION Current evidence provides limited support for the TSH targets recommended by the 2015 ATA guidelines. Optimizing postoperative TSH management should account for individualized factors, including risk stratification, treatment modalities, histologic subtypes, and susceptibility to adverse effects. Future research should prioritize well-designed studies with clearly defined suppression levels and appropriate confounder adjustments, emphasizing personalized approaches to balance therapeutic benefits and adverse effects.
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Affiliation(s)
- Xinxin Song
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xin Zhi
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Linxue Qian
- Department of Ultrasound, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
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Derkach KV, Didenko EA, Sorokoumov VN, Zakharova IO, Shpakov AO. Low-molecular-weight Ligand of the Thyroid-stimulating Hormone Receptor with the Activity of a Partial Agonist and a Negative Allosteric Modulator. DOKL BIOCHEM BIOPHYS 2025; 520:53-57. [PMID: 39847295 DOI: 10.1134/s1607672924600799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/10/2024] [Accepted: 09/10/2024] [Indexed: 01/24/2025]
Abstract
Graves' disease is caused by overactivation of the thyroid-stimulating hormone receptor (TSHR). One approach for its treatment may be the use of negative allosteric modulators (NAM) of TSHR, which normalize TSHR activity and do not cause thyroid hormone (TH) deficiency. The aim of the work was to study the effect of a new compound 5-amino-4-(4-bromophenyl)-2-(methylthio)thieno[2,3-d]pyrimidine-6-carboxylic acid N-tert-butylamide (TPY4) on the basal and TSH-stimulated TH production in cultured FRTL-5 thyrocytes and on basal and thyrotropin-releasing hormone (TRH)-stimulated TH levels in the blood of rats. TPY4 stimulated TH production by thyrocytes and increased TH levels when administered intraperitoneally and orally in rats. It also decreased the TSH-stimulated TH production in thyrocytes and the TRH-stimulated TH levels in rats. Thus, TPY4 is the first known allosteric regulator of TSHR, combining the properties of NAM and a partial agonist, and can be considered as a prototype of drugs for the treatment of Graves' disease.
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Affiliation(s)
- K V Derkach
- I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
| | - E A Didenko
- I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
- Institute of Chemistry, St. Petersburg State University, St. Petersburg, Russia
| | - V N Sorokoumov
- I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
- Institute of Chemistry, St. Petersburg State University, St. Petersburg, Russia
| | - I O Zakharova
- I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia
| | - A O Shpakov
- I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, Russia.
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Parent EE, Gleba JJ, Knight JA, Kenderian SJ, Copland JA, Cai H. Zirconium- 89 Labeled Antibody K1-70 for PET Imaging of Thyroid-stimulating Hormone Receptor Expression in Thyroid Cancer. Mol Imaging Biol 2024; 26:847-857. [PMID: 39174789 DOI: 10.1007/s11307-024-01945-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 08/12/2024] [Accepted: 08/13/2024] [Indexed: 08/24/2024]
Abstract
PURPOSE Thyroid-stimulating hormone receptor (TSHR) is a G-protein coupled receptor that is highly expressed on benign and malignant thyroid tissues. TSHR binding and activation has long been a component of thyroid cancer molecular imaging and radiotherapy, by promoting expression of the sodium-iodide symporter (NIS) and incorporation of I-131 into thyroid hormones. Here, we report the radiosynthesis and preclinical evaluation of a Zirconium-89 (89Zr) labeled TSHR antibody to serve as a positron emission tomography (PET) diagnostic correlate for therapeutic agents targeting TSHR without reliance on NIS. PROCEDURES TSHR human monoclonal antibody K1-70 was conjugated to chelator desferrioxamine-p-benzyl-isothiocyanate, followed by labeling with Zr-89, yielding the radiotracer 89Zr-DFO-TSHR-Ab. The in vitro cellar uptake and binding affinity of 89Zr-DFO-TSHR-Ab were analyzed in three new TSHR stable overexpressing tumor cell lines and their corresponding wild types (WT) with low or no TSHR expression. 89Zr-DFO-TSHR-Ab PET/CT imaging of TSHR expression was evaluated in tumor mouse models bearing one TSHR-positive tumor and other negative control with or without the coinjection of antibody K1-70, and then verified by radiotracer biodistribution study and tumor immunohistochemistry (IHC). RESULTS The conjugate DFO-TSHR-Ab was labeled with Zr-89 at 37 °C for 60 min and purified by PD-10 column in radiochemical yields of 68.8 ± 9.9%, radiochemical purities of 98.7 ± 0.8%, and specific activities of 19.1 ± 2.7 mCi/mg (n = 5). In vitro cell studies showed 89Zr-DFO-TSHR-Ab had significantly high uptake on TSHR expressing tumor cells with nanomolar affinity and high potency. Preclinical PET/CT imaging revealed that 89Zr-DFO-TSHR-Ab selectively detected TSHR expressing thyroid tumors and displayed improved in vivo performance with the coinjection of unlabeled TSHR antibody K1-70 leading to higher uptake in TSHR expressing tumors than parental WT tumors and physiologic tissues; this observation was confirmed by the biodistribution and immunostaining analyses. CONCLUSIONS We synthesized 89Zr-labeled antibody K1-70 as a new radiopharmaceutical for PET imaging of TSHR. 89Zr-DFO-TSHR-Ab has high radioactive uptake and retention in TSHR expressing tumors and cleared quickly from most background tissues in mouse models. Our study demonstrated that 89Zr-DFO-TSHR-Ab has the potential for PET imaging of TSHR-positive thyroid cancer and monitoring TSHR-targeted therapy.
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Affiliation(s)
| | - Justyna J Gleba
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA
| | - Joshua A Knight
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA
| | - Saad J Kenderian
- Department of Oncology, Mayo Clinic, Rochester, MN, USA
- Department of Immunology, Mayo Clinic, Rochester, MN, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA
| | - John A Copland
- Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL, 32224, USA.
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
| | - Hancheng Cai
- Department of Radiology, Mayo Clinic, Jacksonville, FL, USA.
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Zhang Y, Tan Y, Zhang Z, Cheng X, Duan J, Li Y. Targeting Thyroid-Stimulating Hormone Receptor: A Perspective on Small-Molecule Modulators and Their Therapeutic Potential. J Med Chem 2024; 67:16018-16034. [PMID: 39269788 DOI: 10.1021/acs.jmedchem.4c01525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2024]
Abstract
TSHR is a member of the glycoprotein hormone receptors, a subfamily of class A G-protein-coupled receptors and plays pivotal roles in various physiological and pathological processes, particularly in thyroid growth and hormone production. The aberrant TSHR function has been implicated in several human diseases including Graves' disease and orbitopathy, nonautoimmune hyperthyroidism, hypothyroidism, cancer, neurological disorders, and osteoporosis. Consequently, TSHR is recognized as an attractive therapeutic target, and targeting TSHR with small-molecule modulators including agonists, antagonists, and inverse agonists offers great potential for drug discovery. In this perspective, we summarize the structures and biological functions of TSHR as well as the recent advances in the development of small-molecule TSHR modulators, highlighting their chemotypes, mode of actions, structure-activity relationships, characterizations, in vitro/in vivo activities, and therapeutic potential. The challenges, new opportunities, and future directions in this area are also discussed.
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Affiliation(s)
- Yu Zhang
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China
| | - Ye Tan
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China
| | - Zian Zhang
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xi Cheng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 330106, China
| | - Jia Duan
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China
- Center for Structure & Function of Drug Targets, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yi Li
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China
- Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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Sarkar R, Bolel P, Kapoor A, Eliseeva E, Dulcey AE, Templin JS, Wang AQ, Xu X, Southall N, Klubo-Gwiezdzinska J, Neumann S, Marugan JJ, Gershengorn MC. An Orally Efficacious Thyrotropin Receptor Ligand Inhibits Growth and Metastatic Activity of Thyroid Cancers. J Clin Endocrinol Metab 2024; 109:2306-2316. [PMID: 38421044 PMCID: PMC11318999 DOI: 10.1210/clinem/dgae114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 02/06/2024] [Accepted: 02/26/2024] [Indexed: 03/02/2024]
Abstract
CONTEXT Thyroid-stimulating hormone (or thyrotropin) receptor (TSHR) could be a selective target for small molecule ligands to treat thyroid cancer (TC). OBJECTIVE We report a novel, orally efficacious ligand for TSHR that exhibits proliferation inhibitory activity against human TC in vitro and in vivo, and inhibition of metastasis in vivo. METHODS A35 (NCATS-SM4420; NCGC00241808) was selected from a sublibrary of >200 TSHR ligands. Cell proliferation assays including BrdU incorporation and WST-1, along with molecular docking studies were done. In vivo activity of A35 was assessed in TC cell-derived xenograft (CDX) models with immunocompromised (NSG) mice. Formalin-fixed, paraffin-embedded sections of tumor and lung tissues were observed for the extent of cell death and metastasis. RESULTS A35 was shown to stimulate cAMP production in some cell types by activating TSHR but not in TC cells, MDA-T32, and MDA-T85. A35 inhibited proliferation of MDA-T32 and MDA-T85 in vitro and in vivo, and pulmonary metastasis of MDA-T85F1 in mice. In vitro, A35 inhibition of proliferation was reduced by a selective TSHR antagonist. Inhibition of CDX tumor growth without decreases in mouse weights and liver function showed A35 to be efficacious without apparent toxicity. Lastly, A35 reduced levels of Ki67 in the tumors and metastatic markers in lung tissues. CONCLUSION We conclude that A35 is a TSHR-selective inhibitor of TC cell proliferation and metastasis, and suggest that A35 may be a promising lead drug candidate for the treatment of differentiated TC in humans.
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Affiliation(s)
- Rhitajit Sarkar
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Priyanka Bolel
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Abhijeet Kapoor
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
| | - Elena Eliseeva
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Andrés E Dulcey
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
| | - Jay S Templin
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Amy Q Wang
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
| | - Xin Xu
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
| | - Noel Southall
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
| | - Joanna Klubo-Gwiezdzinska
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Susanne Neumann
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Juan J Marugan
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA
| | - Marvin C Gershengorn
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Duan J, He XH, Li SJ, Xu HE. Cryo-electron microscopy for GPCR research and drug discovery in endocrinology and metabolism. Nat Rev Endocrinol 2024; 20:349-365. [PMID: 38424377 DOI: 10.1038/s41574-024-00957-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/29/2024] [Indexed: 03/02/2024]
Abstract
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, with many GPCRs having crucial roles in endocrinology and metabolism. Cryogenic electron microscopy (cryo-EM) has revolutionized the field of structural biology, particularly regarding GPCRs, over the past decade. Since the first pair of GPCR structures resolved by cryo-EM were published in 2017, the number of GPCR structures resolved by cryo-EM has surpassed the number resolved by X-ray crystallography by 30%, reaching >650, and the number has doubled every ~0.63 years for the past 6 years. At this pace, it is predicted that the structure of 90% of all human GPCRs will be completed within the next 5-7 years. This Review highlights the general structural features and principles that guide GPCR ligand recognition, receptor activation, G protein coupling, arrestin recruitment and regulation by GPCR kinases. The Review also highlights the diversity of GPCR allosteric binding sites and how allosteric ligands could dictate biased signalling that is selective for a G protein pathway or an arrestin pathway. Finally, the authors use the examples of glycoprotein hormone receptors and glucagon-like peptide 1 receptor to illustrate the effect of cryo-EM on understanding GPCR biology in endocrinology and metabolism, as well as on GPCR-related endocrine diseases and drug discovery.
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Affiliation(s)
- Jia Duan
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, China.
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
- University of Chinese Academy of Sciences, Beijing, China.
| | - Xin-Heng He
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Shu-Jie Li
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- Department of Traditional Chinese Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - H Eric Xu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
- University of Chinese Academy of Sciences, Beijing, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
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Liang JJ, Feng WJ, Li R, Xu RT, Liang YL. Analysis of the value and safety of thyroid-stimulating hormone in the clinical efficacy of patients with thyroid cancer. World J Clin Cases 2023; 11:1058-1067. [PMID: 36874431 PMCID: PMC9979299 DOI: 10.12998/wjcc.v11.i5.1058] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/04/2023] [Accepted: 01/16/2023] [Indexed: 02/14/2023] Open
Abstract
BACKGROUND Thyroid cancer (TC) is a common malignant tumor in the endocrine system. In recent years, the incidence and recurrence rates of TC have been raising due to increasing work pressure and irregular lifestyles. Thyroid-stimulating hormone (TSH) is a specific parameter for thyroid function screening. This study aims to explore the clinical value of TSH in regulating the progression of TC, so as to find a breakthrough for the early diagnosis and treatment of TC.
AIM To explore the value and safety of TSH in the clinical efficacy of patients with TC.
METHODS 75 patients with TC admitted to the Department of Thyroid and Breast Surgery of our hospital from September 2019 to September 2021 were selected as the observation group, and 50 healthy subjects were selected as the control group during the same period. The control group was treated with conventional thyroid replacement therapy, and the observation group was treated with TSH suppression therapy. The soluble interleukin (IL)-2 receptor (sIL-2R), IL-17, IL-35 levels, free triiodothyronine (FT3), free tetraiodothyronine (FT4), CD3+, CD4+, CD8+, CD44V6, and tumor supplied group of factor (TSGF) levels were observed in the two groups. The occurrence of adverse reactions was compared between the two groups.
RESULTS After treatment with different therapies, the levels of FT3, FT4, CD3+, and CD4+ in the observation group and the control group were higher than those before treatment, while the levels of CD8+, CD44V6, and TSGF were lower than those before treatment, and the differences were statistically significant (P < 0.05). More importantly, the levels of sIL-2R and IL-17 in the observation group were lower than those in the control group after 4 wk of treatment, while the levels of IL-35 were higher than those in the control group, and the differences were statistically significant (P < 0.05). The levels of FT3, FT4, CD3 +, and CD4 + in the observation group were higher than those in the control group, and the levels of CD8+, CD44V6, and TSGF were lower than those in the control group. There was no significant difference in the overall incidence rate of adverse reactions between the two groups (P > 0.05).
CONCLUSION TSH suppression therapy can improve the immune function of patients with TC, lower the CD44V6 and TSGF levels, and improve serum FT3 and FT4 levels. It demonstrated excellent clinical efficacy and a good safety profile.
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Affiliation(s)
- Jian-Jing Liang
- Department of Medicine, Hebei University, Baoding 071000, Hebei Province, China
| | - Wen-Jing Feng
- Department of General Surgery, the Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei Province, China
| | - Ru Li
- Department of Cardiology, First Hospital of Xinji City, Xinji 052300, Hebei Province, China
| | - Run-Tao Xu
- Department of General Surgery, the Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei Province, China
| | - Yu-Long Liang
- Department of General Surgery, the Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei Province, China
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Abstract
Many members of the American Thyroid Association played prominent roles in discovering the various aspects of the hypothalamic-pituitary-thyroid axis. This axis is fundamental for maintaining the normal serum levels of circulating thyroid hormones (THs) and thus the euthyroid state. The pituitary glycoprotein hormone, thyrotropin (TSH), controls the activity of the thyroid gland. Thyrotropin-releasing hormone and the negative feedback mechanism of circulating TH regulate the synthesis and the secretion of TSH. The dynamic interplay of these two dominant mechanisms has essential effects on TSH release. Therefore, the finding of abnormal serum levels of TSH often indicates the presence of a disorder of thyroid gland function. A summary of key historical discoveries in the understanding of the hypothalamic-pituitary axis is presented.
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Nagayama Y, Nishihara E. Thyrotropin receptor antagonists and inverse agonists, and their potential application to thyroid diseases. Endocr J 2022; 69:1285-1293. [PMID: 36171093 DOI: 10.1507/endocrj.ej22-0391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The thyrotropin receptor (TSHR) plays critical roles in thyroid growth and function and in the pathogenesis of several thyroid diseases including Graves' hyperthyroidism and ophthalmopathy, non-autoimmune hyperthyroidism and thyroid cancer. Several low-molecular weight compounds (LMWCs) and anti-TSHR monoclonal antibodies (mAbs) with receptor antagonistic and inverse agonistic activities have been reported. The former binds to the pocket formed by the receptor transmembrane bundle, and the latter to the extracellular TSH binding site. Both are effective inhibitors of TSH/thyroid stimulating antibody-stimulated cAMP and/or hyaluronic acid production in TSHR-expressing cells. Anti-insulin-like growth factor 1 inhibitors are also found to inhibit TSHR signaling. Each agent has advantages and disadvantages; for example, mAbs have a higher affinity and longer half-life but are more costly than LMWCs. At present, mAbs appear most promising, yet the development of more efficacious LMWCs is desirable. These agents are anticipated to be efficacious not only for the above-mentioned diseases but also for resistance to thyroid hormone and have utility for thyroid cancer radionuclide scintigraphy/therapy as a new theranostic.
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Affiliation(s)
- Yuji Nagayama
- Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki 852-8523, Japan
| | - Eijun Nishihara
- Center for Excellence in Thyroid Care, Kuma Hospital, Kobe 650-0011, Japan
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Putilov A. Prospects of Testing Diurnal Profiles of Expressions of TSH-R and Circadian Clock Genes in Thyrocytes for Identification of Preoperative Biomarkers for Thyroid Carcinoma. Int J Mol Sci 2022; 23:12208. [PMID: 36293065 PMCID: PMC9603503 DOI: 10.3390/ijms232012208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/04/2022] [Accepted: 10/11/2022] [Indexed: 11/17/2022] Open
Abstract
Thyroid Nodules (TN) are frequent but mostly benign, and postoperative rate of benign TN attains the values from 70% to 90%. Therefore, there is an urgent need for identification of reliable preoperative diagnosis markers for patients with indeterminate thyroid cytology. In this study, an earlier unexplored design of research on preoperative biomarkers for thyroid malignancies was proposed. Evaluation of reported results of studies addressing the links of thyroid cancer to the circadian clockwork dysfunctions and abnormal activities of Thyroid-Stimulating Hormone (TSH) and its receptor (TSH-R) suggested diagnostic significance of such links. However, there is still a gap in studies of interrelationships between diurnal profiles of expression of circadian clock genes and TSH-R in indeterminate thyroid tissue exposed to different concentrations of TSH. These interrelationships might be investigated in future in vitro experiments on benign and malignant thyrocytes cultivated under normal and challenged TSH levels. Their design requires simultaneous measurement of diurnal profiles of expression of both circadian clock genes and TSH-R. Experimental results might help to bridge previous studies of preoperative biomarkers for thyroid carcinoma exploring diagnostic value of diurnal profiles of serum TSH levels, expression of TSH-R, and expression of circadian clock genes.
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Affiliation(s)
- Arcady Putilov
- Research Group for Math-Modeling of Biomedical Systems, Research Institute for Molecular Biology and Biophysics of the Federal Research Centre for Fundamental and Translational Medicine, 630117 Novosibirsk, Russia; ; Tel.: +49-30-53674643 or +49-30-61290031
- Laboratory of Sleep/Wake Neurobiology, Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences, 117865 Moscow, Russia
- Laboratory of Nanobiotechnology and Biophysics, North-Caucasus Federal University, 355029 Stavropol, Russia
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Vieira IH, Rodrigues D, Paiva I. The Mysterious Universe of the TSH Receptor. Front Endocrinol (Lausanne) 2022; 13:944715. [PMID: 35903283 PMCID: PMC9315062 DOI: 10.3389/fendo.2022.944715] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 06/10/2022] [Indexed: 12/25/2022] Open
Abstract
The thyroid-stimulating hormone receptor (TSH-R) is predominantly expressed in the basolateral membrane of thyrocytes, where it stimulates almost every aspect of their metabolism. Several extrathyroidal locations of the receptor have been found including: the pituitary, the hypothalamus, and other areas of the central nervous system; the periorbital tissue; the skin; the kidney; the adrenal; the liver; the immune system cells; blood cells and vascular tissues; the adipose tissue; the cardiac and skeletal muscles, and the bone. Although the functionality of the receptor has been demonstrated in most of these tissues, its physiological importance is still a matter of debate. A contribution to several pathological processes is evident in some cases, as is the case of Grave's disease in its multiple presentations. Conversely, in the context of other thyroid abnormalities, the contribution of the TSH-R and its ligand is still a matter of debate. This article reviews the several different sites of expression of the TSH-R and its potential role in both physiological and pathological processes.
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12
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Schöneberg T, Liebscher I. Mutations in G Protein-Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches. Pharmacol Rev 2021; 73:89-119. [PMID: 33219147 DOI: 10.1124/pharmrev.120.000011] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
There are approximately 800 annotated G protein-coupled receptor (GPCR) genes, making these membrane receptors members of the most abundant gene family in the human genome. Besides being involved in manifold physiologic functions and serving as important pharmacotherapeutic targets, mutations in 55 GPCR genes cause about 66 inherited monogenic diseases in humans. Alterations of nine GPCR genes are causatively involved in inherited digenic diseases. In addition to classic gain- and loss-of-function variants, other aspects, such as biased signaling, trans-signaling, ectopic expression, allele variants of GPCRs, pseudogenes, gene fusion, and gene dosage, contribute to the repertoire of GPCR dysfunctions. However, the spectrum of alterations and GPCR involvement is probably much larger because an additional 91 GPCR genes contain homozygous or hemizygous loss-of-function mutations in human individuals with currently unidentified phenotypes. This review highlights the complexity of genomic alteration of GPCR genes as well as their functional consequences and discusses derived therapeutic approaches. SIGNIFICANCE STATEMENT: With the advent of new transgenic and sequencing technologies, the number of monogenic diseases related to G protein-coupled receptor (GPCR) mutants has significantly increased, and our understanding of the functional impact of certain kinds of mutations has substantially improved. Besides the classical gain- and loss-of-function alterations, additional aspects, such as biased signaling, trans-signaling, ectopic expression, allele variants of GPCRs, uniparental disomy, pseudogenes, gene fusion, and gene dosage, need to be elaborated in light of GPCR dysfunctions and possible therapeutic strategies.
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Affiliation(s)
- Torsten Schöneberg
- Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, Leipzig, Germany
| | - Ines Liebscher
- Rudolf Schönheimer Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, Leipzig, Germany
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Krause G, Eckstein A, Schülein R. Modulating TSH Receptor Signaling for Therapeutic Benefit. Eur Thyroid J 2020; 9:66-77. [PMID: 33511087 PMCID: PMC7802447 DOI: 10.1159/000511871] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 10/01/2020] [Indexed: 12/14/2022] Open
Abstract
Autoimmune thyroid-stimulating antibodies are activating the thyrotropin receptor (TSHR) in both the thyroid and the eye, but different molecular mechanisms are induced in both organs, leading to Graves' disease (GD) and Graves' orbitopathy (GO), respectively. Therapy with anti-thyroid drugs to reduce hyperthyroidism (GD) by suppressing the biosynthesis of thyroid hormones has only an indirect effect on GO, since it does not causally address pathogenic TSHR activation itself. GO is thus very difficult to treat. The activated TSHR but also the cross-interacting insulin-like growth factor 1 receptor (IGF-1R) contribute to this issue. The TSHR is a heptahelical G-protein-coupled receptor, whereas the IGF-1R is a receptor tyrosine kinase. Despite these fundamental structural differences, both receptors are phosphorylated by G-protein receptor kinases, which enables β-arrestin binding. Arrestins mediate receptor internalization and also activate the mitogen-activated protein kinase pathway. Moreover, emerging results suggest that arrestin plays a critical role in the cross-interaction of the TSHR and the IGF-1R either in their common signaling pathway and/or during an indirect or potential TSHR/IGF-1R interaction. In this review, novel pharmacological strategies with allosteric small-molecule modulators to treat GO and GD on the level of the TSHR and/or the TSHR/IGF-1R cross-interaction will be discussed. Moreover, monoclonal antibody approaches targeting the TSHR or the IGF-1R and thereby preventing activation of either receptor will be presented. Another chapter addresses the immunomodulation to treat GO using TSHR-derived peptides targeting the human leukocyte antigen DR isotope (HLA-DR), which is a feasible approach to tackle GO, since HLA-DR and TSHR are overexpressed in orbital tissues of GO patients.
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Affiliation(s)
- Gerd Krause
- Structural Biology, Leibniz-Forschungsinstitut für molekulare Pharmakologie (FMP), Berlin, Germany
| | - Anja Eckstein
- Department of Ophthalmology, University Hospital Essen, Essen, Germany
| | - Ralf Schülein
- Protein Trafficking, Leibniz-Forschungsinstitut für molekulare Pharmakologie (FMP), Berlin, Germany
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Davies TF, Andersen S, Latif R, Nagayama Y, Barbesino G, Brito M, Eckstein AK, Stagnaro-Green A, Kahaly GJ. Graves' disease. Nat Rev Dis Primers 2020; 6:52. [PMID: 32616746 DOI: 10.1038/s41572-020-0184-y] [Citation(s) in RCA: 212] [Impact Index Per Article: 42.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/19/2020] [Indexed: 02/08/2023]
Abstract
Graves' disease (GD) is an autoimmune disease that primarily affects the thyroid gland. It is the most common cause of hyperthyroidism and occurs at all ages but especially in women of reproductive age. Graves' hyperthyroidism is caused by autoantibodies to the thyroid-stimulating hormone receptor (TSHR) that act as agonists and induce excessive thyroid hormone secretion, releasing the thyroid gland from pituitary control. TSHR autoantibodies also underlie Graves' orbitopathy (GO) and pretibial myxoedema. Additionally, the pathophysiology of GO (and likely pretibial myxoedema) involves the synergism of insulin-like growth factor 1 receptor (IGF1R) with TSHR autoantibodies, causing retro-orbital tissue expansion and inflammation. Although the aetiology of GD remains unknown, evidence indicates a strong genetic component combined with random potential environmental insults in an immunologically susceptible individual. The treatment of GD has not changed substantially for many years and remains a choice between antithyroid drugs, radioiodine or surgery. However, antithyroid drug use can cause drug-induced embryopathy in pregnancy, radioiodine therapy can exacerbate GO and surgery can result in hypoparathyroidism or laryngeal nerve damage. Therefore, future studies should focus on improved drug management, and a number of important advances are on the horizon.
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Affiliation(s)
- Terry F Davies
- Thyroid Research Laboratory, Icahn School of Medicine at Mount Sinai, New York, NY, USA. .,James J. Peters VA Medical Center, New York, NY, USA. .,Mount Sinai Thyroid Center, Mount Sinai Downtown at Union Sq, New York, NY, USA.
| | - Stig Andersen
- Department of Geriatric and Internal Medicine and Arctic Health Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - Rauf Latif
- Thyroid Research Laboratory, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,James J. Peters VA Medical Center, New York, NY, USA
| | - Yuji Nagayama
- Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan
| | - Giuseppe Barbesino
- Thyroid Unit, Division of Endocrinology, Massachusetts General Hospital, Boston, MA, USA
| | - Maria Brito
- Mount Sinai Thyroid Center, Mount Sinai Downtown at Union Sq, New York, NY, USA
| | - Anja K Eckstein
- Department of Ophthalmology, University Duisburg Essen, Essen, Germany
| | - Alex Stagnaro-Green
- Departments of Medicine, Obstetrics and Gynecology and Medical Education, University of Illinois College of Medicine at Rockford, Rockford, IL, USA
| | - George J Kahaly
- Department of Medicine I, Johannes Gutenberg University Medical Centre, Mainz, Germany
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Francis N, Francis T, Lazarus JH, Okosieme OE. Current controversies in the management of Graves' hyperthyroidism. Expert Rev Endocrinol Metab 2020; 15:159-169. [PMID: 32315207 DOI: 10.1080/17446651.2020.1754192] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 04/07/2020] [Indexed: 12/12/2022]
Abstract
Introduction: The management of Graves' disease centers on the use of effective and well-established therapies, namely thionamide antithyroid drugs, radioactive iodine, and thyroidectomy. Optimal treatment strategies are however controversial and vary significantly across centers.Areas covered: This review addresses specific controversies in Graves' disease management including the choice of primary therapy, the approach to women planning pregnancy, and optimal strategies for antithyroid drug and radioiodine therapy.Expert opinion: Important considerations in choosing therapy include treatment efficacy, adverse effects, patient convenience, and resource settings. Recent data suggest that early and effective control of hyperthyroidism is key to improving cardiovascular morbidity and mortality. Studies addressing cancer risk in radioiodine-treated patients face methodological challenges and require clarification in appropriately designed studies. Remission rates with antithyroid drugs are comparable when thionamides are used alone (titration-regimen) or in combination with levothyroxine (block and replace) and can be optimized by extending treatment for at least 12-18 months. Fixed and calculated radioiodine activity regimens are both effective but entail a trade-off between convenience and precision in the administered activity. Optimal preconception strategies are still evolving but ablative treatment in advance of pregnancy offers the most pragmatic means of reducing adverse effects of hyperthyroidism in subsequent pregnancy.
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Affiliation(s)
- Niroshan Francis
- Endocrinology and Diabetes Department, Prince Charles Hospital, Cwm Taf University Health Board, Merthyr Tydfil, UK
| | - Thanuya Francis
- Endocrinology and Diabetes Department, Prince Charles Hospital, Cwm Taf University Health Board, Merthyr Tydfil, UK
| | - John H Lazarus
- Thyroid Research Group, School of Medicine, Cardiff University, Cardiff, UK
| | - Onyebuchi E Okosieme
- Endocrinology and Diabetes Department, Prince Charles Hospital, Cwm Taf University Health Board, Merthyr Tydfil, UK
- Thyroid Research Group, School of Medicine, Cardiff University, Cardiff, UK
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16
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Thyroid eye disease: current and potential medical management. Int Ophthalmol 2020; 40:1035-1048. [PMID: 31919775 DOI: 10.1007/s10792-019-01258-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 12/28/2019] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Thyroid eye disease (TED) is the most frequent extra-thyroid manifestation of Graves' disease and it is more frequent in middle age and in female gender. Nowadays, the causal mechanisms of this disease are not completely understood, but the current available studies suggest that the main causative factor is the thyroid stimulating hormone receptor. MATERIALS AND METHODS To collect reports on TED medical management, a thorough literature search was performed in PubMed database. An additional search was made in Google Scholar to complete the collected items. RESULTS Among the indentified risk factors, tobacco habit is the most relevant. The main criteria to choose a suitable treatment are the activity and severity of the disease. Support measures can be used to improve the patient's symptoms in any phase of the disease. There is a large number of drugs proposed to manage TED, although with different reported rates of success. CONCLUSIONS Currently, the drugs of choice are corticosteroids in moderate-to-severe and in sight-threatening forms. The main problem of corticosteroids is their spectrum of side effects. Therefore, other alternatives are being suggested for medical management of this disease. The efficacy of these alternatives remains unclear.
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Furmaniak J, Sanders J, Clark J, Wilmot J, Sanders P, Li Y, Rees Smith B. Preclinical studies on the toxicology, pharmacokinetics and safety of K1-70 TM a human monoclonal autoantibody to the TSH receptor with TSH antagonist activity. AUTOIMMUNITY HIGHLIGHTS 2019; 10:11. [PMID: 32257067 PMCID: PMC7065368 DOI: 10.1186/s13317-019-0121-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 10/09/2019] [Indexed: 12/27/2022]
Abstract
Background The human monoclonal autoantibody K1-70™ binds to the TSH receptor (TSHR) with high affinity and blocks TSHR cyclic AMP stimulation by TSH and thyroid stimulating autoantibodies. Methods The preclinical toxicology assessment following weekly intravenous (IV) or intramuscular (IM) administration of K1-70™ in rats and cynomolgus monkeys for 29 days was carried out. An assessment of delayed onset toxicity and/or reversibility of toxicity was made during a further 4 week treatment free period. The pharmacokinetic parameters of K1-70™ and the effects of different doses of K1-70™ on serum thyroid hormone levels in the study animals were determined in rats and primates after IV and IM administration. Results Low serum levels of T3 and T4 associated with markedly elevated levels of TSH were observed in the study animals following IV and IM administration of K1-70™. The toxicological findings were attributed to the pharmacology of K1-70™ and were consistent with the hypothyroid state. The no observable adverse effect level (NOAEL) could not be established in the rat study while in the primate study it was 100 mg/kg/dose for both males and females. Conclusions The toxicology, pharmacodynamic and pharmacokinetic data in this preclinical study were helpful in designing the first in human study with K1-70™ administered to subjects with Graves’ disease.
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Affiliation(s)
- Jadwiga Furmaniak
- AV7 Limited, FIRS Laboratories, Parc Ty Glas, Llanishen, Cardiff, CF14 5DU UK
| | - Jane Sanders
- AV7 Limited, FIRS Laboratories, Parc Ty Glas, Llanishen, Cardiff, CF14 5DU UK
| | - Jill Clark
- AV7 Limited, FIRS Laboratories, Parc Ty Glas, Llanishen, Cardiff, CF14 5DU UK
| | - Jane Wilmot
- AV7 Limited, FIRS Laboratories, Parc Ty Glas, Llanishen, Cardiff, CF14 5DU UK
| | - Paul Sanders
- AV7 Limited, FIRS Laboratories, Parc Ty Glas, Llanishen, Cardiff, CF14 5DU UK
| | - Yang Li
- AV7 Limited, FIRS Laboratories, Parc Ty Glas, Llanishen, Cardiff, CF14 5DU UK
| | - Bernard Rees Smith
- AV7 Limited, FIRS Laboratories, Parc Ty Glas, Llanishen, Cardiff, CF14 5DU UK
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18
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Noyes PD, Friedman KP, Browne P, Haselman JT, Gilbert ME, Hornung MW, Barone S, Crofton KM, Laws SC, Stoker TE, Simmons SO, Tietge JE, Degitz SJ. Evaluating Chemicals for Thyroid Disruption: Opportunities and Challenges with in Vitro Testing and Adverse Outcome Pathway Approaches. ENVIRONMENTAL HEALTH PERSPECTIVES 2019; 127:95001. [PMID: 31487205 PMCID: PMC6791490 DOI: 10.1289/ehp5297] [Citation(s) in RCA: 136] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 07/01/2019] [Accepted: 08/13/2019] [Indexed: 05/19/2023]
Abstract
BACKGROUND Extensive clinical and experimental research documents the potential for chemical disruption of thyroid hormone (TH) signaling through multiple molecular targets. Perturbation of TH signaling can lead to abnormal brain development, cognitive impairments, and other adverse outcomes in humans and wildlife. To increase chemical safety screening efficiency and reduce vertebrate animal testing, in vitro assays that identify chemical interactions with molecular targets of the thyroid system have been developed and implemented. OBJECTIVES We present an adverse outcome pathway (AOP) network to link data derived from in vitro assays that measure chemical interactions with thyroid molecular targets to downstream events and adverse outcomes traditionally derived from in vivo testing. We examine the role of new in vitro technologies, in the context of the AOP network, in facilitating consideration of several important regulatory and biological challenges in characterizing chemicals that exert effects through a thyroid mechanism. DISCUSSION There is a substantial body of knowledge describing chemical effects on molecular and physiological regulation of TH signaling and associated adverse outcomes. Until recently, few alternative nonanimal assays were available to interrogate chemical effects on TH signaling. With the development of these new tools, screening large libraries of chemicals for interactions with molecular targets of the thyroid is now possible. Measuring early chemical interactions with targets in the thyroid pathway provides a means of linking adverse outcomes, which may be influenced by many biological processes, to a thyroid mechanism. However, the use of in vitro assays beyond chemical screening is complicated by continuing limits in our knowledge of TH signaling in important life stages and tissues, such as during fetal brain development. Nonetheless, the thyroid AOP network provides an ideal tool for defining causal linkages of a chemical exerting thyroid-dependent effects and identifying research needs to quantify these effects in support of regulatory decision making. https://doi.org/10.1289/EHP5297.
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Affiliation(s)
- Pamela D Noyes
- National Center for Environmental Assessment, Office of Research and Development (ORD), U.S. Environmental Protection Agency (EPA), Washington, DC, USA
| | - Katie Paul Friedman
- National Center for Computational Toxicology, ORD, U.S. EPA, Research Triangle Park, North Carolina, USA
| | - Patience Browne
- Environment Health and Safety Division, Environment Directorate, Organisation for Economic Co-operation and Development (OECD), Paris, France
| | - Jonathan T Haselman
- Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory (NHEERL), ORD, U.S. EPA, Duluth, Minnesota, USA
| | - Mary E Gilbert
- Toxicity Assessment Division, NHEERL, ORD, U.S. EPA, Research Triangle Park, North Carolina, USA
| | - Michael W Hornung
- Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory (NHEERL), ORD, U.S. EPA, Duluth, Minnesota, USA
| | - Stan Barone
- Office of Pollution Prevention and Toxics, Office of Chemical Safety and Pollution Prevention, U.S. EPA, Washington, DC, USA
| | - Kevin M Crofton
- National Center for Computational Toxicology, ORD, U.S. EPA, Research Triangle Park, North Carolina, USA
| | - Susan C Laws
- Toxicity Assessment Division, NHEERL, ORD, U.S. EPA, Research Triangle Park, North Carolina, USA
| | - Tammy E Stoker
- Toxicity Assessment Division, NHEERL, ORD, U.S. EPA, Research Triangle Park, North Carolina, USA
| | - Steven O Simmons
- National Center for Computational Toxicology, ORD, U.S. EPA, Research Triangle Park, North Carolina, USA
| | - Joseph E Tietge
- Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory (NHEERL), ORD, U.S. EPA, Duluth, Minnesota, USA
| | - Sigmund J Degitz
- Mid-Continent Ecology Division, National Health and Environmental Effects Research Laboratory (NHEERL), ORD, U.S. EPA, Duluth, Minnesota, USA
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Pearce SH, Dayan C, Wraith DC, Barrell K, Olive N, Jansson L, Walker-Smith T, Carnegie C, Martin KF, Boelaert K, Gilbert J, Higham CE, Muller I, Murray RD, Perros P, Razvi S, Vaidya B, Wernig F, Kahaly GJ. Antigen-Specific Immunotherapy with Thyrotropin Receptor Peptides in Graves' Hyperthyroidism: A Phase I Study. Thyroid 2019; 29:1003-1011. [PMID: 31194638 PMCID: PMC6648194 DOI: 10.1089/thy.2019.0036] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Background: Graves' disease is one of the most common autoimmune conditions, but treatment remains imperfect. This study explores the first-in-human use of antigen-specific immunotherapy with a combination of two thyrotropin receptor (TSHR) peptides (termed ATX-GD-59) in Graves' hyperthyroidism. Methods: Twelve participants (11 female) with previously untreated mild to moderate Graves' hyperthyroidism were enrolled in a Phase I open label trial to receive 10 doses of ATX-GD-59 administered intradermally over an 18-week period. Adverse events, tolerability, changes in serum free thyroid hormones, and TSHR autoantibodies were measured. Results: Ten subjects received all 10 doses of ATX-GD-59, five (50%) of whom had free triiodothyronine within the reference interval by the 18-week visit. Two further subjects had improved free thyroid hormones by the end of the study (7/10 responders), whereas three subjects showed worsening thyrotoxicosis during the study. Serum TSHR autoantibody concentrations reduced during the study and correlated with changes in free thyroid hormones (r = 0.85, p = 0.002 for TSHR autoantibody vs. free triiodothyronine). Mild injection-site swelling and pain were the most common adverse events. Conclusions: These preliminary data suggest that ATX-GD-59 is a safe and well-tolerated treatment. The improvement in free thyroid hormones in 70% of subjects receiving the medication suggests potential efficacy as a novel treatment for Graves' hyperthyroidism.
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Affiliation(s)
- Simon H.S. Pearce
- Institute for Genetic Medicine, Newcastle University, and Newcastle Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom
| | - Colin Dayan
- Thyroid Research Group, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - David C. Wraith
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham United Kingdom
- Apitope Technology (Bristol) Ltd., Chepstow, United Kingdom
- Apitope International NV, Diepenbeek, Belgium
| | - Kevin Barrell
- Apitope Technology (Bristol) Ltd., Chepstow, United Kingdom
| | - Natalie Olive
- Apitope Technology (Bristol) Ltd., Chepstow, United Kingdom
| | | | | | | | | | - Kristien Boelaert
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham United Kingdom
| | - Jackie Gilbert
- Department of Endocrinology, King's College Hospital, London, United Kingdom
| | - Claire E. Higham
- Department of Endocrinology, Christie Hospital NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester, United Kingdom
| | - Ilaria Muller
- Thyroid Research Group, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Robert D. Murray
- Department of Endocrinology, St. James's University Hospital, Leeds, United Kingdom
| | - Petros Perros
- Endocrine Unit, Newcastle Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom
| | - Salman Razvi
- Institute for Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Bijay Vaidya
- Macleod Diabetes & Endocrine Centre, Royal Devon and Exeter Hospital, Exeter, United Kingdom
| | - Florian Wernig
- Department of Endocrinology, Imperial College, London, United Kingdom
| | - George J. Kahaly
- Department of Medicine I, Johannes Gutenberg University Medical Center, Mainz, Germany
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Marcinkowski P, Hoyer I, Specker E, Furkert J, Rutz C, Neuenschwander M, Sobottka S, Sun H, Nazare M, Berchner-Pfannschmidt U, von Kries JP, Eckstein A, Schülein R, Krause G. A New Highly Thyrotropin Receptor-Selective Small-Molecule Antagonist with Potential for the Treatment of Graves' Orbitopathy. Thyroid 2019; 29:111-123. [PMID: 30351237 DOI: 10.1089/thy.2018.0349] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND The thyrotropin receptor (TSHR) is the target for autoimmune thyroid stimulating antibodies (TSAb) triggering hyperthyroidism. Whereas elevated thyroid hormone synthesis by the thyroid in Graves' disease can be treated by antithyroid agents, for the pathogenic activation of TSHR in retro-orbital fibroblasts of the eye, leading to Graves' orbitopathy (GO), no causal TSHR directed therapy is available. METHODS Due to the therapeutic gap for severe GO, TSHR inhibitors were identified by high-throughput screening in Chinese hamster ovary cells expressing the TSHR. Stereo-selective synthesis of the screening hits led to the molecule S37, which contains seven chiral centers. Enantiomeric separation of the molecule S37 resulted in the enantiopure molecule S37a-a micro-molar antagonist of thyrotropin-induced cyclic adenosine monophosphate accumulation in HEK 293 cells expressing the TSHR. RESULTS The unique rigid bent shape of molecule S37a may mediate the observed high TSHR selectivity. Most importantly, the closely related follitropin and lutropin receptors were not affected by this compound. S37a not only inhibits the TSHR activation by thyrotropin itself but also activation by monoclonal TSAb M22 (human), KSAb1 (murine), and the allosteric small-molecule agonist C2. Disease-related ex vivo studies in HEK 293 cells expressing the TSHR showed that S37a also inhibits cyclic adenosine monophosphate formation by oligoclonal TSAb, which are highly enriched in GO patients' sera. Initial in vivo pharmacokinetic studies revealed no toxicity of S37a and a remarkable 53% oral bioavailability in mice. CONCLUSION In summary, a novel highly selective inhibitor for the TSHR is presented, which has promising potential for further development for the treatment of GO.
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Affiliation(s)
| | - Inna Hoyer
- 1 Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
| | - Edgar Specker
- 1 Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
| | - Jens Furkert
- 1 Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
| | - Claudia Rutz
- 1 Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
| | | | - Sebastian Sobottka
- 1 Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
| | - Han Sun
- 1 Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
| | - Marc Nazare
- 1 Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
| | | | | | - Anja Eckstein
- 2 Department of Ophthalmology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Ralf Schülein
- 1 Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
| | - Gerd Krause
- 1 Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
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Kahaly GJ, Bartalena L, Hegedüs L, Leenhardt L, Poppe K, Pearce SH. 2018 European Thyroid Association Guideline for the Management of Graves' Hyperthyroidism. Eur Thyroid J 2018; 7:167-186. [PMID: 30283735 PMCID: PMC6140607 DOI: 10.1159/000490384] [Citation(s) in RCA: 494] [Impact Index Per Article: 70.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 05/24/2018] [Indexed: 12/12/2022] Open
Abstract
Graves' disease (GD) is a systemic autoimmune disorder characterized by the infiltration of thyroid antigen-specific T cells into thyroid-stimulating hormone receptor (TSH-R)-expressing tissues. Stimulatory autoantibodies (Ab) in GD activate the TSH-R leading to thyroid hyperplasia and unregulated thyroid hormone production and secretion. Diagnosis of GD is straightforward in a patient with biochemically confirmed thyrotoxicosis, positive TSH-R-Ab, a hypervascular and hypoechoic thyroid gland (ultrasound), and associated orbitopathy. In GD, measurement of TSH-R-Ab is recommended for an accurate diagnosis/differential diagnosis, prior to stopping antithyroid drug (ATD) treatment and during pregnancy. Graves' hyperthyroidism is treated by decreasing thyroid hormone synthesis with the use of ATD, or by reducing the amount of thyroid tissue with radioactive iodine (RAI) treatment or total thyroidectomy. Patients with newly diagnosed Graves' hyperthyroidism are usually medically treated for 12-18 months with methimazole (MMI) as the preferred drug. In children with GD, a 24- to 36-month course of MMI is recommended. Patients with persistently high TSH-R-Ab at 12-18 months can continue MMI treatment, repeating the TSH-R-Ab measurement after an additional 12 months, or opt for therapy with RAI or thyroidectomy. Women treated with MMI should be switched to propylthiouracil when planning pregnancy and during the first trimester of pregnancy. If a patient relapses after completing a course of ATD, definitive treatment is recommended; however, continued long-term low-dose MMI can be considered. Thyroidectomy should be performed by an experienced high-volume thyroid surgeon. RAI is contraindicated in Graves' patients with active/severe orbitopathy, and steroid prophylaxis is warranted in Graves' patients with mild/active orbitopathy receiving RAI.
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Affiliation(s)
- George J. Kahaly
- Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany
- *Prof. George J. Kahaly, JGU Medical Center, DE-55101 Mainz (Germany), E-Mail
| | - Luigi Bartalena
- Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Lazlo Hegedüs
- Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark
| | - Laurence Leenhardt
- Thyroid and Endocrine Tumors Unit, Pitié Salpêtrière Hospital, Sorbonne University, Paris, France
| | - Kris Poppe
- Endocrine Unit, CHU Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Simon H. Pearce
- Department of Endocrinology, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
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Suwansaksri N, Preechasuk L, Kunavisarut T. Nonthionamide Drugs for the Treatment of Hyperthyroidism: From Present to Future. Int J Endocrinol 2018; 2018:5794054. [PMID: 29849619 PMCID: PMC5937426 DOI: 10.1155/2018/5794054] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Accepted: 03/11/2018] [Indexed: 12/20/2022] Open
Abstract
Hyperthyroidism is a common endocrine disease. Although thionamide antithyroid drugs are the cornerstone of hyperthyroidism treatment, some patients cannot tolerate this drug class because of its serious side effects including agranulocytosis, hepatotoxicity, and vasculitis. Therefore, nonthionamide antithyroid drugs (NTADs) still have an important role in controlling hyperthyroidism in clinical practice. Furthermore, some situations such as thyroid storm or preoperative preparation require a rapid decrease in thyroid hormone by combination treatment with multiple classes of antithyroid drugs. NTADs include iodine-containing compounds, lithium carbonate, perchlorate, glucocorticoid, and cholestyramine. In this narrative review, we summarize the mechanisms of action, indications, dosages, and side effects of currently used NTADs for the treatment of hyperthyroidism. In addition, we also describe the state-of-the-art in future drugs under development including rituximab, small-molecule ligands (SMLs), and monoclonal antibodies with a thyroid-stimulating hormone receptor (TSHR) antagonist effect.
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Affiliation(s)
| | - Lukana Preechasuk
- Siriraj Diabetes Center, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Tada Kunavisarut
- Division of Endocrine and Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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Rossi M, Taddei AR, Fasciani I, Maggio R, Giorgi F. The cell biology of the thyroid-disrupting mechanism of dichlorodiphenyltrichloroethane (DDT). J Endocrinol Invest 2018. [PMID: 28639207 DOI: 10.1007/s40618-017-0716-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Dichlorodiphenyltrichloroethane (DDT) is an organochlorine known for its pesticide properties and for its negative effects on human health. It was banned in most countries for its toxicity to the endocrine system, but due to its persistence at clinically relevant concentrations in both soil and animal tissues, DDT is still linked to several health and social problems. METHODS We have previously shown that DDT exposure is causally related to the extracellular release of vesicular organelles such as microvesicles and/or exosomes by using immunocytochemistry with gold-tagged antibodies and various fluorescent membrane markers. RESULTS It is now well recognized that microvesicles and/or exosomes organelles are implicated in cell-to-cell communication, and that they are fundamental elements for transferring proteins, RNA, DNA, lipids and transcriptional factors among cells. In this short review, we discussed the role of extracellular vesicle formation in the thyroid-disrupting mechanism of DDT. In particular, we described how DDT, by dislodging the thyrotropin hormone (TSH) receptor from the raft containing compartments of the cells, prevents its activation and internalization. CONCLUSION Based on our earlier finding and on the large body of evidence here reviewed, we propose that DDT-induced formation of extracellular vesicles containing the TSH receptor could be directly involved in the development of autoimmune responses against the TSH receptor and that, therefore, their release could lead to the development of the Graves' disease.
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Affiliation(s)
- M Rossi
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - A R Taddei
- Section of Electron Microscopy, Great Equipment Center, University of Tuscia, Viterbo, Italy
| | - I Fasciani
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | - R Maggio
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy.
| | - F Giorgi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
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Khan I, Okosieme O, Lazarus J. Antithyroid drug therapy in pregnancy: a review of guideline recommendations. Expert Rev Endocrinol Metab 2017; 12:269-278. [PMID: 30058885 DOI: 10.1080/17446651.2017.1338944] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The antithyroid drugs, Carbimazole, Methimazole, and Propylthiouracil remain the mainstay of Graves' disease management in pregnancy. A series of Clinical Practice Guidelines aimed at optimising fetal and maternal outcomes in women with Graves' disease have been published in recent years. Areas covered: This review examines existing guideline recommendations on antithyroid drug management of Graves' disease in pregnancy. Expert commentary: Recent guidelines have been shaped by expanding knowledge of the adverse effect profiles of antithyroid drugs on the developing fetus. A core management strategy is to limit fetal exposure to excess thyroid hormones and to curtail adverse drug effects through effective preconception and peri-conception management. Propylthiouracil is the recommended treatment in the first trimester of pregnancy but there is uncertainty regarding antithyroid drug choices in women who continue to require treatment in later pregnancy. Further studies are needed to fully evaluate the risks of congenital anomalies following intrauterine thionamide exposure.
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Affiliation(s)
| | - Onyebuchi Okosieme
- a Cardiff University School of Medicine
- b Cwm Taf, University Health Board - Diabetes Department , Prince Charles Hospital
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25
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Place RF, Krieger CC, Neumann S, Gershengorn MC. Inhibiting thyrotropin/insulin-like growth factor 1 receptor crosstalk to treat Graves' ophthalmopathy: studies in orbital fibroblasts in vitro. Br J Pharmacol 2017; 174:328-340. [PMID: 27987211 DOI: 10.1111/bph.13693] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 12/05/2016] [Accepted: 12/14/2016] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND AND PURPOSE Crosstalk between thyrotropin (TSH) receptors and insulin-like growth factor 1 (IGF-1) receptors initiated by activation of TSH receptors could be important in the development of Graves' ophthalmopathy (GO). Specifically, TSH receptor activation alone is sufficient to stimulate hyaluronic acid (HA) secretion, a major component of GO, through both IGF-1 receptor-dependent and -independent pathways. Although an anti-IGF-1 receptor antibody is in clinical trials, its effectiveness depends on the relative importance of IGF-1 versus TSH receptor signalling in GO pathogenesis. EXPERIMENTAL APPROACH TSH and IGF-1 receptor antagonists were used to probe TSH/IGF-1 receptor crosstalk in primary cultures of Graves' orbital fibroblasts (GOFs) following activation with monoclonal TSH receptor antibody, M22. Inhibition of HA secretion following TSH receptor stimulation was measured by modified HA elisa. KEY RESULTS TSH receptor antagonist, ANTAG3 (NCGC00242364), inhibited both IGF-1 receptor -dependent and -independent pathways at all doses of M22; whereas IGF-1 receptor antagonists linsitinib and 1H7 (inhibitory antibody) lost efficacy at high M22 doses. Combining TSH and IGF-1 receptor antagonists exhibited Loewe additivity within the IGF-1 receptor-dependent component of the M22 concentration-response. Similar effects were observed in GOFs activated by autoantibodies from GO patients' sera. CONCLUSIONS AND IMPLICATIONS Our data support TSH and IGF-1 receptors as therapeutic targets for GO, but reveal putative conditions for anti-IGF-1 receptor resistance. Combination treatments antagonizing both receptors yield additive effects by inhibiting crosstalk triggered by TSH receptor stimulatory antibodies. Combination therapy may be an effective strategy for dose reduction and/or compensate for any loss of anti-IGF-1 receptor efficacy.
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Affiliation(s)
- Robert F Place
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Christine C Krieger
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Susanne Neumann
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Marvin C Gershengorn
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
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26
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Kleinau G, Worth CL, Kreuchwig A, Biebermann H, Marcinkowski P, Scheerer P, Krause G. Structural-Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work. Front Endocrinol (Lausanne) 2017; 8:86. [PMID: 28484426 PMCID: PMC5401882 DOI: 10.3389/fendo.2017.00086] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 04/03/2017] [Indexed: 12/21/2022] Open
Abstract
The thyroid-stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs). TSHR and its endogenous ligand thyrotropin (TSH) are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy) or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination via X-ray crystallography. This review summarizes available knowledge (as of December 2016) concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other class A GPCRs to understand the molecular activation mechanisms of this receptor comprehensively. Finally, limitations of current knowledge and lack of information are discussed highlighting the need for intensified efforts toward TSHR structure elucidation.
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Affiliation(s)
- Gunnar Kleinau
- Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin, Berlin, Germany
- Group Protein X-Ray Crystallography and Signal Transduction, Institute of Medical Physics and Biophysics, Charité-Universitätsmedizin, Berlin, Germany
| | | | - Annika Kreuchwig
- Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany
| | - Heike Biebermann
- Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin, Berlin, Germany
| | | | - Patrick Scheerer
- Group Protein X-Ray Crystallography and Signal Transduction, Institute of Medical Physics and Biophysics, Charité-Universitätsmedizin, Berlin, Germany
| | - Gerd Krause
- Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany
- *Correspondence: Gerd Krause,
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27
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Topliss DJ. Clinical Update in Aspects of the Management of Autoimmune Thyroid Diseases. Endocrinol Metab (Seoul) 2016; 31:493-499. [PMID: 28029020 PMCID: PMC5195823 DOI: 10.3803/enm.2016.31.4.493] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Revised: 11/11/2016] [Accepted: 11/17/2016] [Indexed: 12/24/2022] Open
Abstract
Aspects of autoimmune thyroid disease updated in this review include: immunoglobulin G4 (IgG4)-related thyroid disease (Riedel's thyroiditis, fibrosing variant of Hashimoto's thyroiditis, IgG4-related Hashimoto's thyroiditis, and Graves' disease with elevated IgG4 levels); recent epidemiological studies from China and Denmark indicating that excess iodine increases the incidence of Hashimoto's thyroiditis and hypothyroidism; immunomodulatory agents (ipilimumab, pembrolizumab, nivolumab) activate immune response by inhibiting T-cell surface receptors which down-regulate immune response, i.e., cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1 pathways; alemtuzumab is a humanised monoclonal antibody to CD52 which causes immune depletion and thyroid autoimmune disease especially Graves' hyperthyroidism; small molecule ligand (SML) agonists which activate receptors, SML neutral antagonists, which inhibit receptor activation by agonists, and SML inverse agonists which inhibit receptor activation by agonists and inhibit constitutive agonist independent signaling have been identified. SML antagonism of thyroid-stimulating hormone-receptor stimulatory antibody could treat Graves' hyperthyroidism and Graves' ophthalmopathy; and thyroxine treatment of subclinical hypothyroidism can produce iatrogenic subclinical hyperthyroidism with the risk of atrial fibrillation and osteoporosis. The increased risk of harm from subclinical hyperthyroidism may be stronger than the potential benefit from treatment of subclinical hypothyroidism.
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Affiliation(s)
- Duncan J Topliss
- Department of Endocrinology and Diabetes, The Alfred, Melbourne, Australia
- Department of Medicine, Monash University, Melbourne, Australia.
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28
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Kelly T, Denmark L, Lieberman DZ. Elevated levels of circulating thyroid hormone do not cause the medical sequelae of hyperthyroidism. Prog Neuropsychopharmacol Biol Psychiatry 2016; 71:1-6. [PMID: 27302764 DOI: 10.1016/j.pnpbp.2016.06.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 05/24/2016] [Accepted: 06/01/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND Clinicians have been reluctant to use high dose thyroid (HDT) to treat affective disorders because high circulating levels of thyroid hormone have traditionally been equated with hyperthyroidism, and understood as the cause of the medical sequelae of hyperthyroidism, such as osteoporosis and cardiac abnormalities. This conclusion is not supported by (HDT) research. METHODS A literature review of research related to the morbidity and mortality of HDT treatment was performed. RESULTS There exists a large body of research involving the use of HDT treatment to prevent the recurrence of differentiated thyroid cancer and to treat affective disorders. A review of this literature finds a lack of support for HDT as a cause of osteoporosis, nor is there support for an increase in morbidity or mortality associated with HDT. This finding contrasts with the well-established morbidity and mortality associated with Graves' disease, thyroiditis, and other endogenous forms of hyperthyroidism. DISCUSSION The lack of evidence that exogenous HDT causes osteoporosis, cardiac abnormalities or increases mortality compared with the significant morbidity and mortality of hyperthyroidism requires an alternative cause for the medical sequelae of hyperthyroidism. One possibility is an autoimmune mechanism. CONCLUSION High circulating levels of thyroid hormone is not the cause of the sequela of hyperthyroidism. The reluctance to using high dose thyroid is unwarranted.
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Affiliation(s)
- Tammas Kelly
- George Washington University, Department of Psychiatry and Behavioral Sciences, 2120 L St NW, Suite 600, Washington, DC 20037, United States(1); The Depression & Bipolar Clinic of Colorado, 400 East Horsetooth Road, Suite 300, Fort Collins, CO 80525, United States(2).
| | - Lawrence Denmark
- The Depression & Bipolar Clinic of Colorado, 400 East Horsetooth Road, Suite 300, Fort Collins, CO 80525, United States(2)
| | - Daniel Z Lieberman
- George Washington University, Department of Psychiatry and Behavioral Sciences, 2120 L St NW, Suite 600, Washington, DC 20037, United States(1)
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29
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Okosieme OE, Lazarus JH. Current trends in antithyroid drug treatment of Graves' disease. Expert Opin Pharmacother 2016; 17:2005-17. [PMID: 27615550 DOI: 10.1080/14656566.2016.1232388] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
INTRODUCTION Graves' hyperthyroidism is associated with significant morbidity and mortality risk. The thionamides, methimazole, its pro-drug derivative carbimazole, and propylthiouracil, remain a cornerstone of management. Yet despite decades of use, optimal strategies for maximising treatment response and curtailing adverse effect risk remains uncertain. AREAS COVERED We reviewed the current literature on the evidence based medical management of Graves' disease. Specifically, we evaluated current approaches to the use of thionamides, adjunctive therapies, and potential novel agents for controlling Graves' hyperthyroidism. EXPERT OPINION Primary medical therapy is successful in less than 50% of cases and so careful selection of patients for medical treatment based on a combination of pathological and pragmatic considerations is essential. Carbimazole or methimazole is the treatment of choice in the non-pregnant population driven by its more favourable pharmacokinetic and adverse effect profile over propylthiouracil. In pregnancy the choice of treatment is less straightforward and an approach that minimises undue fetal exposure to all thionamides should be adopted. Additional data is needed on the value of adjunctive therapies including potassium perchlorate, iodides, glucocorticoids, lithium, and cholestyramine. Novel agents directed against pathogenetic targets including TSH receptor blocking monoclonal antibodies and small molecule antagonists may hold promise for the future.
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Affiliation(s)
- Onyebuchi E Okosieme
- a Thyroid Research Group, Institute of Molecular and Experimental Medicine , School of Medicine, Cardiff University , Cardiff , UK.,b Endocrine and Diabetes Department , Prince Charles Hospital, Cwm Taf University Health Board , Merthyr Tydfil , UK
| | - John H Lazarus
- a Thyroid Research Group, Institute of Molecular and Experimental Medicine , School of Medicine, Cardiff University , Cardiff , UK
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30
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Yoo WS, Chung HK. Recent Advances in Autoimmune Thyroid Diseases. Endocrinol Metab (Seoul) 2016; 31:379-385. [PMID: 27586448 PMCID: PMC5053048 DOI: 10.3803/enm.2016.31.3.379] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 07/06/2016] [Accepted: 07/13/2016] [Indexed: 12/13/2022] Open
Abstract
Autoimmune thyroid disease (AITD) includes hyperthyroid Graves disease, hypothyroid autoimmune thyroiditis, and subtle subclinical thyroid dysfunctions. AITD is caused by interactions between genetic and environmental predisposing factors and results in autoimmune deterioration. Data on polymorphisms in the AITD susceptibility genes, related environmental factors, and dysregulation of autoimmune processes have accumulated over time. Over the last decade, there has been progress in the clinical field of AITD with respect to the available diagnostic and therapeutic methods as well as clinical consensus. The updated clinical guidelines allow practitioners to identify the most reasonable and current approaches for proper management. In this review, we focus on recent advances in understanding the genetic and environmental pathogenic mechanisms underlying AITD and introduce the updated set of clinical guidelines for AITD management. We also discuss other aspects of the disease such as management of subclinical thyroid dysfunction, use of levothyroxine plus levotriiodothyronine in the treatment of autoimmune hypothyroidism, risk assessment of long-standing antithyroid drug therapy in recurrent Graves' hyperthyroidism, and future research needs.
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Affiliation(s)
- Won Sang Yoo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea
| | - Hyun Kyung Chung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea.
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31
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Yen PM. TSHβv-A New Bone to Pick. Endocrinology 2016; 157:3402-4. [PMID: 27580809 DOI: 10.1210/en.2016-1519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Affiliation(s)
- Paul M Yen
- Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore 169016, Singapore
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32
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Campi I, Vannucchi G, Salvi M. THERAPY OF ENDOCRINE DISEASE: Endocrine dilemma: management of Graves' orbitopathy. Eur J Endocrinol 2016; 175:R117-33. [PMID: 27032693 DOI: 10.1530/eje-15-1164] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Accepted: 03/31/2016] [Indexed: 12/22/2022]
Abstract
Management of Graves' orbitopathy (GO) must be based on the correct assessment of activity and severity of the disease. Activity is usually assessed with the Clinical Activity Score, whereas severity is classified according to a European Group On Graves' Orbitopathy (EUGOGO) consensus statement as mild, moderate-to-severe, and sight-threatening. Myopathic and chronic congestive forms are uncommon clinical presentations of GO. Restoration and maintenance of stable euthyroidism are recommended in the presence of GO.In moderate-to-severe disease, steroids have been widely employed and have shown to possess an anti-inflammatory activity, but about 20-30% of patients are not responsive and present recurrence. Some novel immunosuppressors have already been employed in clinical studies and have shown interesting results, although the lack of randomized and controlled trials suggests caution for their use in clinical practice. Potential targets for therapy in GO are the thyroid-stimulating hormone and the insulin-like growth factor 1 receptor on the fibroblasts, inflammatory cytokines, B and T cells, and the PIK3/mTORC1 signaling cascades for adipogenesis. A recent open study has shown that tocilizumab, an anti-sIL-6R antibody, inactivates GO. Consistent reports on the efficacy of rituximab have recently been challenged by randomized controlled trials.As the main goal of treatment is the well-being of the patient, the therapeutic strategy should be addressed to better suit the patient needs, more than improving one or more biological parameters. The increasing availability of new therapies will expand the therapeutic options for GO patients and allow the clinician to really personalize the treatment to better suit the patients' personal needs.
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Affiliation(s)
- Irene Campi
- Graves' Orbitopathy CenterEndocrinology, Fondazione IRCCS Cà Granda, Milan, Italy
| | - Guia Vannucchi
- Graves' Orbitopathy CenterEndocrinology, Fondazione IRCCS Cà Granda, Milan, Italy
| | - Mario Salvi
- Graves' Orbitopathy CenterEndocrinology, Fondazione IRCCS Cà Granda, Milan, Italy
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33
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Neumann S, Padia U, Cullen MJ, Eliseeva E, Nir EA, Place RF, Morgan SJ, Gershengorn MC. An Enantiomer of an Oral Small-Molecule TSH Receptor Agonist Exhibits Improved Pharmacologic Properties. Front Endocrinol (Lausanne) 2016; 7:105. [PMID: 27512388 PMCID: PMC4961696 DOI: 10.3389/fendo.2016.00105] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 07/18/2016] [Indexed: 11/13/2022] Open
Abstract
We are developing an orally available small-molecule, allosteric TSH receptor (TSHR) agonist for follow-up diagnostics of patients with thyroid cancer. The agonist C2 (NCGC00161870) that we have studied so far is a racemic mixture containing equal amounts of two enantiomers, E1 and E2. As enantiomers of many drugs exhibit different pharmacologic properties, we assessed the properties of E1 and E2. We separated the two enantiomers by chiral chromatography and determined E2 as the (S)-(+) isomer via crystal structure analysis. E1 and E2 were shown to bind differently to a homology model of the transmembrane domain of TSHR in which E2 was calculated to exhibit lower binding energy than E1 and was, therefore, predicted to be more potent than E1. In HEK293 cells expressing human TSHRs, C2, E1, and E2 were equally efficacious in stimulating cAMP production, but their potencies were different. E2 was more potent (EC50 = 18 nM) than C2 (EC50 = 46 nM), which was more potent than E1 (EC50 = 217 nM). In primary cultures of human thyrocytes, C2, E1, and E2 stimulated increases in thyroperoxidase mRNA of 92-, 55-, and 137-fold and in sodium-iodide symporter mRNA of 20-, 4-, and 121-fold above basal levels, respectively. In mice, C2 stimulated an increase in radioactive iodine uptake of 1.5-fold and E2 of 2.8-fold above basal level, whereas E1 did not have an effect. C2 stimulated an increase in serum T4 of 2.4-fold, E1 of 1.9-fold, and E2 of 5.6-fold above basal levels, and a 5-day oral dosing regimen of E2 increased serum T4 levels comparable to recombinant human TSH (rhTSH, Thyrogen(®)). Thus, E2 is more effective than either C2 or E1 in stimulating thyroid function and as efficacious as rhTSH in vivo. E2 represents the next step toward developing an oral drug for patients with thyroid cancer.
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Affiliation(s)
- Susanne Neumann
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
- *Correspondence: Susanne Neumann,
| | - Umesh Padia
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Mary Jane Cullen
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Elena Eliseeva
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Eshel A. Nir
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Robert F. Place
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Sarah J. Morgan
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Marvin C. Gershengorn
- Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
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Abstract
PURPOSE OF REVIEW This article provides an update on the role of the essential trace element selenium and its interaction with the other trace elements iodine and iron that together contribute to adequate thyroid hormone status. Synthesis, secretion, metabolism and action of thyroid hormone in target tissues depend on a balanced nutritional availability or supplementation of these elements. Selenium status is altered in benign and malignant thyroid diseases and various selenium compounds have been used to prevent or treat widespread diseases such as goiter, autoimmune thyroid disease or thyroid cancer. RECENT FINDINGS Several studies, most with still too low numbers of cases, indicate that selenium administration in both autoimmune thyroiditis (Hashimoto thyroiditis) and mild Graves' disease improves clinical scores and well-being of patients and reduces thyroperoxidase antibody titers. However, published results are still conflicting depending on basal selenium status, dose, time and form of selenium used for intervention. Evidence for sex-specific selenium action, lack of beneficial effects in pregnancy and contribution of genetic polymorphisms (selenoprotein S) has been presented. SUMMARY Adequate nutritional supply of selenium that saturates expression of circulating selenoprotein P, together with optimal iodine and iron intake, is required for a healthy and functional thyroid during development, adolescence, adulthood and aging.
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Affiliation(s)
- Josef Köhrle
- Institute of Experimental Endocrinology, Charité University Medicine Berlin, Berlin, Germany
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35
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Banga JP, Moshkelgosha S, Berchner-Pfannschmidt U, Eckstein A. Modeling Graves' Orbitopathy in Experimental Graves' Disease. Horm Metab Res 2015; 47:797-803. [PMID: 26287396 DOI: 10.1055/s-0035-1555956] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Graves' orbitopathy (GO), also known as thyroid eye disease is an inflammatory disease of the orbital tissue of the eye that arises as a consequence of autoimmune thyroid disease. The central feature of the disease is the production of antibodies to the thyrotropin hormone receptor (TSHR) that modulate the function of the receptor leading to autoimmune hyperthyroidism and GO. Over the years, all viable preclinical models of Graves' disease have been incomplete and singularly failed to progress in the treatment of orbital complications. A new mouse model of GO based upon immunogenic presentation of human TSHR A-subunit plasmid by close field electroporation is shown to lead to induction of prolonged functional antibodies to TSHR resulting in chronic disease with subsequent progression to GO. The stable preclinical GO model exhibited pathologies reminiscent of human disease characterized by orbital remodeling by inflammation and adipogenesis. Inflammatory lesions characterized by CD3+ T cells and macrophages were localized in the orbital muscle tissue. This was accompanied by extensive adipogenesis of orbital fat in some immune animals. Surprisingly, other signs of orbital involvement were reminiscent of eyelid inflammation involving chemosis, with dilated and congested orbital blood vessels. More recently, the model is replicated in the author's independent laboratories. The pre-clinical model will provide the basis to study the pathogenic and regulatory roles of immune T and B cells and their subpopulations to understand the initiation, pathophysiology, and progression of GO.
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Affiliation(s)
- J P Banga
- Faculty of Life Sciences & Medicine, King's College London, The Rayne Institute, London, UK
| | - S Moshkelgosha
- Faculty of Life Sciences & Medicine, King's College London, The Rayne Institute, London, UK
| | | | - A Eckstein
- Department of Ophthalmology, University of Duisburg-Essen, Essen, Germany
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Intranasal and Intramuscular Administration of Lysine-Palmitoylated Peptide 612–627 of Thyroid-Stimulating Hormone Receptor Increases the Level of Thyroid Hormones in Rats. Int J Pept Res Ther 2015. [DOI: 10.1007/s10989-014-9452-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Latif R, Ali MR, Ma R, David M, Morshed SA, Ohlmeyer M, Felsenfeld DP, Lau Z, Mezei M, Davies TF. New small molecule agonists to the thyrotropin receptor. Thyroid 2015; 25:51-62. [PMID: 25333622 PMCID: PMC4291085 DOI: 10.1089/thy.2014.0119] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Novel small molecular ligands (SMLs) to the thyrotropin receptor (TSHR) have potential as improved molecular probes and as therapeutic agents for the treatment of thyroid dysfunction and thyroid cancer. METHODS To identify novel SMLs to the TSHR, we developed a transcription-based luciferase-cAMP high-throughput screening system and we screened 48,224 compounds from a 100K library in duplicate. RESULTS We obtained 62 hits using the cut-off criteria of the mean±three standard deviations above the baseline. Twenty molecules with the greatest activity were rescreened against the parent CHO-luciferase cell for nonspecific activation, and we selected two molecules (MS437 and MS438) with the highest potency for further study. These lead molecules demonstrated no detectible cross-reactivity with homologous receptors when tested against luteinizing hormone (LH)/human chorionic gonadotropin receptor and follicle stimulating hormone receptor-expressing cells. Molecule MS437 had a TSHR-stimulating potency with an EC50 of 13×10(-8) M, and molecule MS438 had an EC50 of 5.3×10(-8) M. The ability of these small molecule agonists to bind to the transmembrane domain of the receptor and initiate signal transduction was suggested by their activation of a chimeric receptor consisting of an LHR ectodomain and a TSHR transmembrane. Molecular modeling demonstrated that these molecules bound to residues S505 and E506 for MS438 and T501 for MS437 in the intrahelical region of transmembrane helix 3. We also examined the G protein activating ability of these molecules using CHO cells co-expressing TSHRs transfected with luciferase reporter vectors in order to measure Gsα, Gβγ, Gαq, and Gα12 activation quantitatively. The MS437 and MS438 molecules showed potent activation of Gsα, Gαq, and Gα12 similar to TSH, but neither the small molecule agonists nor TSH showed activation of the Gβγ pathway. The small molecules MS437 and MS438 also showed upregulation of thyroglobulin (Tg), sodium iodine symporter (NIS), and TSHR gene expression. CONCLUSIONS Pharmacokinetic analysis of MS437 and MS438 indicated their pharmacotherapeutic potential, and their intraperitoneal administration to normal female mice resulted in significantly increased serum thyroxine levels, which could be maintained by repeated treatments. These molecules can therefore serve as lead molecules for further development of powerful TSH agonists.
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Affiliation(s)
- Rauf Latif
- Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai and the James J. Peters VA Medical Center, New York, New York
| | - M. Rejwan Ali
- Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai and the James J. Peters VA Medical Center, New York, New York
| | - Risheng Ma
- Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai and the James J. Peters VA Medical Center, New York, New York
| | - Martine David
- Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai and the James J. Peters VA Medical Center, New York, New York
| | - Syed A. Morshed
- Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai and the James J. Peters VA Medical Center, New York, New York
| | - Michael Ohlmeyer
- Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Dan P. Felsenfeld
- Integrated Screening Core, Experimental Therapeutics Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Zerlina Lau
- Integrated Screening Core, Experimental Therapeutics Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Mihaly Mezei
- Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Terry F. Davies
- Thyroid Research Unit, Department of Medicine, Icahn School of Medicine at Mount Sinai and the James J. Peters VA Medical Center, New York, New York
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Szkudlinski MW. New Frontier in Glycoprotein Hormones and Their Receptors Structure-Function. Front Endocrinol (Lausanne) 2015; 6:155. [PMID: 26539160 PMCID: PMC4609891 DOI: 10.3389/fendo.2015.00155] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 09/18/2015] [Indexed: 01/27/2023] Open
Abstract
Last two decades of structure-function studies performed in numerous laboratories provided substantial progress in understanding basic science, physiological, pathophysiological, pharmacological, and comparative aspects of glycoprotein hormones (GPHs) and their cognate receptors. Multiple concepts and models developed based on experimental data in the past stood the test of time and have been, at least in part, confirmed and/or remained compatible with the new structures resolved at the atomic level. Major advances in understanding of the ligand-receptor relationships are heralding the dawn of a new era for GPHs and their receptors, although many basic questions still remain unanswered. This article examines retrospectively several basic science aspects of GPH super-agonists and related "biosuperiors" in a broader context of the advances in the ligand-receptor structure-function relationships and new mechanistic models generated based on the structure elucidation. Due to selective focus of my comments and perspectives in certain parts, the reader is directed to the most relevant publications and reviews in the field for more comprehensive analyses.
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Affiliation(s)
- Mariusz W. Szkudlinski
- Trophogen Inc., Rockville, MD, USA
- *Correspondence: Mariusz W. Szkudlinski, Trophogen Inc., 9714 Medical Center Drive, Rockville, MD, USA,
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Abstract
PURPOSE OF REVIEW In recent years, immunosuppressive therapy, as an alternative to corticosteroids, has been proposed as novel agents which target the various antigens involved in the pathogenesis of Graves' ophthalmopathy. Although the lack of randomized and controlled studies suggests caution in generalizing results, some data show interesting results. RECENT FINDINGS Potential targets for immune therapy in Graves' ophthalmopathy are the antigens expressed on the target organ of inflammation, namely the receptor and the insulin growth factor -1 receptor on fibroblasts, inflammatory cytokines, and B and T cells. The most promising results are observed with small thyroid stimulating hormone receptor molecules interacting with the receptor on thyrocytes and fibroblasts and with the anti-IGF-1 receptor antibody teprotumumab. A recent open study with tocilizumab, an anti-soluble interleukin-6 receptor, has shown inactivation of Graves' ophthalmopathy. Consistent reports on the efficacy of rituximab will have to be confirmed by randomized controlled trials, which are now in progress. SUMMARY Current clinical practice for Graves' ophthalmopathy will greatly benefit from the availability of immunosuppressors that act as disease-modifying drugs, as compared to steroids, the current standard treatment for Graves' ophthalmopathy. Rituximab seems to be a good candidate, as preliminary results from ongoing randomized trials suggest good efficacy with a relative well tolerated profile.
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Affiliation(s)
- Mario Salvi
- Graves' Orbitopathy Unit, Fondazione Cà Granda, IRCCS, Department of Clinical and Community Sciences, University of Milan, Milan, Italy
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Ulloa-Aguirre A, Reiter E, Bousfield G, Dias JA, Huhtaniemi I. Constitutive activity in gonadotropin receptors. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2014; 70:37-80. [PMID: 24931192 DOI: 10.1016/b978-0-12-417197-8.00002-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Constitutively active mutants (CAMs) of gonadotropin receptors are, in general, rare conditions. Luteinizing hormone-choriogonadotropin receptor (LHCGR) CAMs provoke the dramatic phenotype of familial gonadotropin-independent isosexual male-limited precocious puberty, whereas in females, there is not yet any identified phenotype. Only one isolated follicle-stimulating hormone receptor (FSHR) CAM (Asp567Gly) has so far been detected in a single male patient, besides other FSHR weak CAMs linked to pregnancy-associated ovarian hyperstimulation syndrome or to impaired desensitization and internalization. Several animal models have been developed for studying enhanced gonadotropin action; in addition to unraveling valuable new information about the possible phenotypes of isolated FSHR and LHCGR CAMs in women, the information obtained from these mouse models has served multiple translational goals, including the development of new diagnostic and therapeutic targets as well as the prediction of phenotypes for mutations not yet identified in humans. Mutagenesis and computational studies have shed important information on the physiopathogenic mechanisms leading to constitutive activity of gonadotropin receptors; a common feature in these receptor CAMs is the release of stabilizing interhelical interactions between transmembrane domains (TMDs) 3 and 6 leading to an increase, with respect to the wild-type receptor, in the solvent accessibility at the cytosolic extension of TMDs 3, 5, and 6, which involves the highly conserved Glu/Asp-Arg-Tyr/Trp sequence. In this chapter, we summarize the structural features, functional consequences, and mechanisms that lead to constitutive activation of gonadotropin receptor CAMs and provide information on pharmacological approaches that might potentially modulate gonadotropin receptor CAM function.
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Affiliation(s)
- Alfredo Ulloa-Aguirre
- Studium Consortium for Research and Training in Reproductive Sciences (sCORTS), Tours, France; Research Support Network, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán" and Universidad Nacional Autónoma de México, México D.F., Mexico.
| | - Eric Reiter
- Studium Consortium for Research and Training in Reproductive Sciences (sCORTS), Tours, France; BIOS Group, INRA, UMR85, Unité Physiologie de la Reproduction et des Comportements, Nouzilly, France; CNRS, UMR7247, Nouzilly, France; Université François Rabelais, Tours, France
| | - George Bousfield
- Studium Consortium for Research and Training in Reproductive Sciences (sCORTS), Tours, France; Department of Biological Sciences, Wichita State University, Wichita, Kansas, USA
| | - James A Dias
- Studium Consortium for Research and Training in Reproductive Sciences (sCORTS), Tours, France; Department of Biomedical Sciences, School of Public Health, University at Albany, Albany, New York, USA
| | - Ilpo Huhtaniemi
- Studium Consortium for Research and Training in Reproductive Sciences (sCORTS), Tours, France; Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom
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Neumann S, Nir EA, Eliseeva E, Huang W, Marugan J, Xiao J, Dulcey AE, Gershengorn MC. A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice. Endocrinology 2014; 155:310-4. [PMID: 24169564 PMCID: PMC3868809 DOI: 10.1210/en.2013-1835] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Because the TSH receptor (TSHR) plays an important role in the pathogenesis of thyroid disease, a TSHR antagonist could be a novel treatment. We attempted to develop a small molecule, drug-like antagonist of TSHR signaling that is selective and active in vivo. We synthesized NCGC00242364 (ANTAG3) by chemical modification of a previously reported TSHR antagonist. We tested its potency, efficacy, and selectivity in a model cell system in vitro by measuring its activity to inhibit stimulation of cAMP production stimulated by TSH, LH, or FSH. We tested the in vivo activity of ANTAG3 by measuring its effects to lower serum free T4 and thyroid gene expression in female BALB/c mice continuously treated with ANTAG3 for 3 days and given low doses of TRH continuously or stimulated by a single administration of a monoclonal thyroid-stimulating antibody M22. ANTAG3 was selective for TSHR inhibition; half-maximal inhibitory doses were 2.1 μM for TSHR and greater than 30 μM for LH and FSH receptors. In mice treated with TRH, ANTAG3 lowered serum free T4 by 44% and lowered mRNAs for sodium-iodide cotransporter and thyroperoxidase by 75% and 83%, respectively. In mice given M22, ANTAG3 lowered serum free T4 by 38% and lowered mRNAs for sodium-iodide cotransporter and thyroperoxidase by 73% and 40%, respectively. In conclusion, we developed a selective TSHR antagonist that is effective in vivo in mice. This is the first report of a small-molecule TSHR antagonist active in vivo and may lead to a drug to treat Graves' disease.
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Affiliation(s)
- Susanne Neumann
- Laboratory of Endocrinology and Receptor Biology (S.N., E.N., E.E., M.C.G.), National Institute of Diabetes and Digestive and Kidney Diseases, and Division of Pre-Clinical Innovation (W.H., J.M., J.X., A.E.D.), National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892
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Kleinau G, Biebermann H. Constitutive activities in the thyrotropin receptor: regulation and significance. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2014; 70:81-119. [PMID: 24931193 DOI: 10.1016/b978-0-12-417197-8.00003-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
The thyroid-stimulating hormone receptor (TSHR, or thyrotropin receptor) is a family A G protein-coupled receptor. It not only binds thyroid-stimulating hormone (TSH, or thyrotropin) but also interacts with autoantibodies under pathological conditions. The TSHR and TSH are essential for thyroid growth and function and thus for all thyroid hormone-associated physiological superordinated processes, including metabolism and development of the central nervous system. In vitro studies have found that the TSHR permanently stimulates ligand-independent (constitutive) activation of Gs, which ultimately leads to intracellular cAMP accumulation. Furthermore, a vast variety of constitutively activating mutations of TSHR-at more than 50 different amino acid positions-have been reported to enhance basal signaling. These lead in vivo to a "gain-of-function" phenotype of nonautoimmune hyperthyroidism or toxic adenomas. Moreover, many naturally occurring inactivating mutations are known to cause a "loss-of-function" phenotype, resulting in resistance to thyroid hormone or hyperthyrotropinemia. Several of these mutations are also characterized by impaired basal signaling, and these are designated here as "constitutively inactivating mutations" (CIMs). More than 30 amino acid positions with CIMs have been identified so far. Moreover, the permanent TSHR signaling capacity can also be blocked by inverse agonistic antibodies or small drug-like molecules, which both have a potential for clinical usage. In this chapter, information on constitutive activity in the TSHR is described, including up- and downregulation, linked protein conformations, physiological and pathophysiological conditions, and related intracellular signaling.
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Affiliation(s)
- Gunnar Kleinau
- Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
| | - Heike Biebermann
- Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Berlin, Germany
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Galofré JC, Chacón AM, Latif R. Targeting thyroid diseases with TSH receptor analogs. ACTA ACUST UNITED AC 2013; 60:590-8. [DOI: 10.1016/j.endonu.2012.12.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2012] [Accepted: 12/18/2012] [Indexed: 10/27/2022]
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Kleinau G, Neumann S, Grüters A, Krude H, Biebermann H. Novel insights on thyroid-stimulating hormone receptor signal transduction. Endocr Rev 2013; 34:691-724. [PMID: 23645907 PMCID: PMC3785642 DOI: 10.1210/er.2012-1072] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The TSH receptor (TSHR) is a member of the glycoprotein hormone receptors, a subfamily of family A G protein-coupled receptors. The TSHR is of great importance for the growth and function of the thyroid gland. The TSHR and its endogenous ligand TSH are pivotal proteins with respect to a variety of physiological functions and malfunctions. The molecular events of TSHR regulation can be summarized as a process of signal transduction, including signal reception, conversion, and amplification. The steps during signal transduction from the extra- to the intracellular sites of the cell are not yet comprehensively understood. However, essential new insights have been achieved in recent years on the interrelated mechanisms at the extracellular region, the transmembrane domain, and intracellular components. This review contains a critical summary of available knowledge of the molecular mechanisms of signal transduction at the TSHR, for example, the key amino acids involved in hormone binding or in the structural conformational changes that lead to G protein activation or signaling regulation. Aspects of TSHR oligomerization, signaling promiscuity, signaling selectivity, phenotypes of genetic variations, and potential extrathyroidal receptor activity are also considered, because these are relevant to an understanding of the overall function of the TSHR, including physiological, pathophysiological, and pharmacological perspectives. Directions for future research are discussed.
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Affiliation(s)
- Gunnar Kleinau
- Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Ostring 3, Augustenburger Platz 1, 13353 Berlin, Germany.
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Abstract
PURPOSE OF REVIEW To provide information on the role of the essential trace element selenium, which enables appropriate thyroid hormone synthesis, secretion, and metabolism, and to discuss supplementation with various selenium compounds, which prevent thyroid diseases such as goiter and exert beneficial effects in thyroid autoimmune diseases. RECENT FINDINGS Selenium administration in both autoimmune thyroiditis (M. Hashimoto) and mild Graves' disease improves clinical scores and well-being of patients and reduces autoimmune antibody titres in several prospective, placebo-controlled supplementation studies. SUMMARY Adequate nutritional supply of selenium, together with the two other essential trace elements iodine and iron, is required for a healthy thyroid during development and adolescence, as well as in the adult and aging populations.
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Affiliation(s)
- Josef Köhrle
- Institute of Experimental Endocrinology, Charité University Medicine Berlin, Germany.
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Molecular sampling of the allosteric binding pocket of the TSH receptor provides discriminative pharmacophores for antagonist and agonists. Biochem Soc Trans 2013; 41:213-7. [PMID: 23356285 PMCID: PMC3561627 DOI: 10.1042/bst20120319] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The TSHR (thyrotropin receptor) is activated endogenously by the large hormone thyrotropin and activated pathologically by auto-antibodies. Both activate and bind at the extracellular domain. Recently, SMLs (small-molecule ligands) have been identified, which bind in an allosteric binding pocket within the transmembrane domain. Modelling driven site-directed mutagenesis of amino acids lining this pocket led to the delineation of activation and inactivation sensitive residues. Modified residues showing CAMs (constitutively activating mutations) indicate signalling-sensitive positions and mark potential trigger points for agonists. Silencing mutations lead to an impairment of basal activity and mark contact points for antagonists. Mapping these residues on to a structural model of TSHR indicates locations where an SML may switch the receptor to an inactive or active conformation. In the present article, we report the effects of SMLs on these signalling-sensitive amino acids at the TSHR. Surprisingly, the antagonistic effect of SML compound 52 was reversed to an agonistic effect, when tested at the CAM Y667A. Switching agonism to antagonism and the reverse by changing either SMLs or residues covering the binding pocket provides detailed knowledge about discriminative pharmacophores. It prepares the basis for rational optimization of new high-affinity antagonists to interfere with the pathogenic activation of the TSHR.
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Szychta P, Szychta W, Gesing A, Lewiński A, Karbownik-Lewińska M. TSH receptor antibodies have predictive value for breast cancer - retrospective analysis. Thyroid Res 2013; 6:8. [PMID: 23680448 PMCID: PMC3662571 DOI: 10.1186/1756-6614-6-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 05/05/2013] [Indexed: 11/22/2022] Open
Abstract
Background Associations between breast cancer and thyroid disorders are reported in numerous studies. Relationships between thyroperoxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb) and breast cancer have been previously demonstrated. However, no analysis has been performed concerning an association between thyrotropin (TSH) receptor antibodies (TSHRAb) and breast cancer. The aim of the study was to evaluate the prevalence of breast cancer or benign breast tumors in patients with Graves’ disease and to analyze a possible relationship between Graves’ disease and these two groups of breast diseases with emphasis to epidemiology and laboratory findings. Patients and methods Clinical and laboratory details of 2003 women hospitalized for endocrine disorders were retrospectively analyzed, using an unpaired Student’s t-test, logistic regression analysis, χ2 test of independence or the two-sided ratio comparison test. Results The coexistence of Graves’ disease and breast cancer was statistically significant. We observed TSHRAb and TgAb more frequently in patients with breast cancer. We found that TSHRAb is the only variable possessing predictive value for breast cancer. Conclusions The strong relationship between Graves’ disease and breast cancer is proposed. We suggest that TSHRAb could be described as a positive determinant of breast cancer. The present data call attention to the usefulness of screening for breast cancer in long-term follow-up of patients with autoimmune thyroid disorders, especially of those with Graves’ disease. Similarly, screening for autoimmune thyroid disorders should be performed in patients with nodular breast disease. Additionally, the article draws ideas for further research in order to develop targeted treatment for more successful outcome in patients with breast cancer.
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Affiliation(s)
- Paweł Szychta
- Department of Oncological Endocrinology, Medical University of Lodz, 7/9 Zeligowski St,, 90-752, Lodz, Poland.
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Turcu AF, Kumar S, Neumann S, Coenen M, Iyer S, Chiriboga P, Gershengorn MC, Bahn RS. A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of Graves ophthalmopathy. J Clin Endocrinol Metab 2013; 98:2153-9. [PMID: 23482611 PMCID: PMC3644605 DOI: 10.1210/jc.2013-1149] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Graves ophthalmopathy (GO) is an autoimmune disorder characterized by increased adipogenesis and hyaluronan (HA) production by orbital fibroblasts. Circulating autoantibodies (thyroid-stimulating antibodies [TSAbs]) directed at the thyrotropin receptor (TSHR) on these cells stimulate or augment these cellular processes. A recently developed drug-like small molecule inverse agonist of TSHR, NCGC00229600, termed 1, binds to TSHR and blocks basal and stimulated signal transduction. OBJECTIVE The purpose of this article was to determine whether 1 might inhibit HA production and relevant signaling pathways in orbital fibroblasts cultured in the presence of monoclonal TSAbs or bovine TSH (bTSH). DESIGN Primary cultures of undifferentiated GO orbital fibroblasts (n = 13) were untreated or treated with a TSAb (M22 or MS-1) or bTSH in serum-free medium, with or without 1 or a TSHR neutral antagonist, NCGC00242595, termed 2, which does not inhibit basal signaling but does inhibit stimulated signaling. MAIN OUTCOME MEASURES cAMP production, Akt phosphorylation (Ser473pAkt in media and immunoblotting for pAkt/total Akt), and HA production were analyzed. RESULTS Compound 1 inhibited basal cAMP, pAkt, and HA production and that stimulated by M22 in undifferentiated orbital fibroblasts. Inhibition of HA production was dose-dependent, with a half-maximal inhibitory dose of 830 nM. This compound also inhibited MS-1- and bTSH-stimulated cAMP, pAkt, and HA production. Compound 2 did not inhibit basal HA production but did inhibit M22-stimulated HA production. CONCLUSIONS Because cAMP, pAkt, and HA production are fibroblast functions that are activated via TSHR signaling and are important in the pathogenesis of GO, small molecule TSHR antagonists may prove to be effective in the treatment or prevention of the disease in the future.
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MESH Headings
- Adipose Tissue, White/drug effects
- Adipose Tissue, White/immunology
- Adipose Tissue, White/metabolism
- Adipose Tissue, White/pathology
- Antibodies, Monoclonal/metabolism
- Cell Dedifferentiation
- Cells, Cultured
- Cyclic AMP/metabolism
- Drug Inverse Agonism
- Eye/drug effects
- Eye/immunology
- Eye/metabolism
- Eye/pathology
- Fibroblasts/drug effects
- Fibroblasts/immunology
- Fibroblasts/metabolism
- Fibroblasts/pathology
- Graves Ophthalmopathy/drug therapy
- Graves Ophthalmopathy/immunology
- Graves Ophthalmopathy/metabolism
- Graves Ophthalmopathy/pathology
- Humans
- Hyaluronic Acid/metabolism
- Immunoglobulins, Thyroid-Stimulating/metabolism
- Osmolar Concentration
- Phosphorylation/drug effects
- Protein Processing, Post-Translational/drug effects
- Proto-Oncogene Proteins c-akt/metabolism
- Pyridines/pharmacology
- Quinazolinones/pharmacology
- Receptors, Thyrotropin/agonists
- Receptors, Thyrotropin/antagonists & inhibitors
- Receptors, Thyrotropin/metabolism
- Signal Transduction/drug effects
- Thyrotropin/agonists
- Thyrotropin/antagonists & inhibitors
- Thyrotropin/pharmacology
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Affiliation(s)
- Adina F Turcu
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55902, USA
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Dietrich JW, Landgrafe G, Fotiadou EH. TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis. J Thyroid Res 2012; 2012:351864. [PMID: 23365787 PMCID: PMC3544290 DOI: 10.1155/2012/351864] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Accepted: 11/21/2012] [Indexed: 12/11/2022] Open
Abstract
This paper provides the reader with an overview of our current knowledge of hypothalamic-pituitary-thyroid feedback from a cybernetic standpoint. Over the past decades we have gained a plethora of information from biochemical, clinical, and epidemiological investigation, especially on the role of TSH and other thyrotropic agonists as critical components of this complex relationship. Integrating these data into a systems perspective delivers new insights into static and dynamic behaviour of thyroid homeostasis. Explicit usage of this information with mathematical methods promises to deliver a better understanding of thyrotropic feedback control and new options for personalised diagnosis of thyroid dysfunction and targeted therapy, also by permitting a new perspective on the conundrum of the TSH reference range.
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Affiliation(s)
- Johannes W. Dietrich
- Lab XU44, Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum (UK RUB), Bürkle-de-la-Camp-Platz 1, 44789 Bochum, NRW, Germany
| | - Gabi Landgrafe
- Lab XU44, Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum (UK RUB), Bürkle-de-la-Camp-Platz 1, 44789 Bochum, NRW, Germany
- Klinik für Allgemein- und Visceralchirurgie, Agaplesion Bethesda Krankenhaus Wuppertal gGmbH, Hainstraße 35, 42109 Wuppertal, NRW, Germany
| | - Elisavet H. Fotiadou
- Lab XU44, Medical Hospital I, Bergmannsheil University Hospitals, Ruhr University of Bochum (UK RUB), Bürkle-de-la-Camp-Platz 1, 44789 Bochum, NRW, Germany
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