J Biol Chem (1996) 271:294006. Ligand-dependent activation of classical kinase-dependent signaling with -arrestin recruitment provokes GRK-dependent serine phosphorylation located in the IGF-IR C-domain. IGFBP-5 also has IGF-independent activities and is even detected in the nucleus. Nuclear Localization and Actions of the Insulin-Like Growth Factor 1 (IGF-1) System Components: Transcriptional Regulation and DNA Damage Response. All had eye disease 9 months in duration. De Meyts P, Sajid W, Palsgaard J, Theede A, Gaugain L, Aladdin H, et al. (A) Thyroid-stimulating immunoglobulins (TSI) drive the over-production of thyroid hormones by activating the thyrotropin receptor (TSHR), thus overriding the normal regulatory role of thyrotropin on the process. Physiologic Effects of Growth Hormone A critical concept in understanding growth hormone activity is that it has two distinct types of effects: Direct effects are the result of growth hormone binding its receptor on target cells. Wang L, Shao YY, Ballock RT. Animals harboring the mutant transcription factor, Pit-1, (Snell dwarf mice), exhibit multiple deficiencies in anterior pituitary hormones resulting in defective B cell development (77). Tramontano D, Cushing GW, Moses AC, Ingbar SH. T3 and IGF-I influence divergently GH synthesis and release from cultured pituitary cells in monolayer (66). Several important exclusions in the profiles of eligible patients who were enrolled in those studies have resulted in additional questions needing answers during the post-approval period. IGF-I and insulin in combination with TSH can suppress the transcription of the Mac-2BP gene in these cells by decreasing the binding of an upstream specific factor to a gene promoter site (41). IGF-1 is an anabolic hormone mainly synthesized in the liver and local expressed in peripheral tissues [] under the control of pituitary growth hormone (GH).IGF-1 in turn seems to modulate GH secretion through a negative feedback mechanism [].GH/IGF-1 signaling is essential for normal growth in children and for the maintenance of anabolic . With regard to thyroid cancer, the IGF-I pathway has been directly implicated in the transformation of thyroid epithelial cells (45). Changes in Serum Thyroid Hormones Levels and Their Mechanisms During Long-Term Growth Hormone (GH) Replacement Therapy in GH Deficient Children. Thyroid enlargement in acromegaly can be nodular, multinodular or diffuse (48, 54). When cultivated from the peripheral circulation, fibrocytes express several thyroid-specific proteins, including thyrotropin receptor (TSHR), thyroglobulin, thyroperoxidase and sodium-iodide symporter. Clipboard, Search History, and several other advanced features are temporarily unavailable. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. An important goal of this medical therapy is to lessen reliance on either routine surgical rehabilitation for chronic disease or urgent surgical intervention in sight-threatening TAO. Immunoglobulin G From Patients With Graves Disease Induces interleukin-16 and RANTES Expression in Cultured Human Thyrocytes: A Putative Mechanism for T-Cell Infiltration of the Thyroid in Autoimmune Disease. -. eCollection 2023. While IGF-I synthesis was initially considered to be driven by GH as a systemically active mediator, recent decades have witnessed increasing insight into its roles as a paracrine and autocrine factor. Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Vasilcanu D, Girnita A, et al. Novel metabolic and physiological functions of branched chain amino doi: 10.1210/en.2005-1375, 40. Randomized Phase II Study of Erlotinib in Combination With Placebo or R1507, a Monoclonal Antibody to Insulin-Like Growth Factor-1 Receptor, for Advanced-Stage non-Small-Cell Lung Cancer. The relationship between growth hormone and biological aging is supported by studies demonstrating that growth hormone administration to old animals and humans raises plasma IGF-1 and results in increases in skeletal muscle and lean body mass, a decrease in adiposity, increased immune function, improvements in learning and memory, and increases . 77. Westermark K, Alm J, Skottner A, Karlsson A. Saji M, Tsushima T, Isozaki O, Murakami H, Ohba Y, Sato K, et al. Those open questions are also under study. Douglas RS, Kahaly GJ, Patel A, Sile S, Thompson EHZ, Perdok R, et al. doi: 10.1172/JCI113672, 97. Reprinted with permission. Careers. Hppener JW, Steenbergh PH, Slebos RJ, de Pagter-Holthuizen P, Roos BA, Jansen M, et al. The author declares US Patents covering the use of IGF-1 receptor inhibitors in autoimmune disease and consultancy for Horizon Therapeutics Consultant Immunovant. Among these, IGFs impact the thyroid and the hormones that it generates. doi: 10.3892/ijo.2.6.961. Imbalance in IGF production or function is associated with various pathologic conditions, including . Their initial report was soon followed by more complete characterizations from that group as well as studies emanating from other laboratories (95). The Occurrence of Thyroid Focal Lesions and a Need for Fine Needle Aspiration Biopsy in Patients With Acromegaly Due to an Increased Risk of Thyroid Cancer. doi: 10.1210/endo-124-5-2277, 76. Among these cells are CD34+ fibroblasts which we propose derive from fibrocytes, monocyte-derived progenitor cells that traffic from bone marrow. Both responses must have occurred in the more severely affected (study) eye assessed at 24 weeks. Pritchard J, Tsui S, Horst N, Cruikshank WW, Smith TJ. Several well-travelled IGF-IR signaling pathways cross-talk with those downstream from TSHR in thyroid epithelial cells. doi: 10.1007/BF03346614, 7. Expression of Insulin-Like Growth Factor-I and -II Genes in Rat Medullary Thyroid Carcinoma. Bethel C, Saadi H, Hout W, Vitullo J, Aron D. Secretion and Binding of Insulin-Like Growth Factor-I by a Human Medullary-Thyroid Carcinoma Cell-Line. doi: 10.1530/eje.0.1320605, 32. Figure 5 (A) Trial profile describing enrollment, randomization, and follow-up. J Mol Endocrinol (2007) 38:61925. For instance, interpretation of laboratory thyroid testing in this condition can be complicated. (B) Change from baseline in proptosis (least squares mean standard error). So too, is this pathway of central importance to the signaling initiated through IGF-I. doi: 10.1074/jbc.M611526200, 92. In contrast, the insulin receptor is the primary regulator of metabolism and carbohydrate handling. doi: 10.1097/MED.0b013e32833c8942, 89. Its first cousin, sulfation factor, was first described nearly four decades later by Daughaday and colleagues (3). Cacicedo L, de los Frailes MT, Lorenzo MJ, Sanchez Franco F. Pituitary and Peripheral Insulin-Like Growth Factor-I Regulation by Thyroid Hormone. The author is grateful to Ms. Dana Barnhart and Ms. Linda Polonsky for their outstanding help in the preparation of this manuscript. Polychronakos C, Guyda HJ, Patel B, Posner BI. Both possess heterotetrameric protein structures comprising extracellular domains containing ligand binding sites located in two subunits. The capacity for IGF-IR to crosstalk with additional proteins is becoming increasingly recognized (121). Iglesias-Osma MC, Blanco EJ, Carretero-Hernandez M, Catalano-Iniesta L, Sanchez-Robledo V, Garcia-Barrado MJ, et al. FEBS Lett (1987) 215:1226. Douglas RS, Brix TH, Hwang CJ, Hegedus L, Smith TJ. Brenner-Gati L, Berg KA, Gershengorn MC. Front Immunol. Each patient was randomized to receive either placebo or teprotumumab in a 1:1 ratio. That study demonstrated that synovial fibroblasts from patients with RA responded to their own IgGs as well as to GD-IgG in inducing IL-16 and RANTES expression. Similar associations have been identified in other receptor complexes. Enrollment criteria were stringently skewed toward early disease since a priori reasoning suggested that the most active patients were more likely to respond. doi: 10.1111/bcp.12228, 126. J. Med, Douglas R.S, Kahaly G.J., Patel A., Sile E.H.Z., Thompson R. etal. doi: 10.1074/jbc.M800211200, 90. Morgan DO, Edman JC, Standring DN, Fried VA, Smith MC, Roth RA, et al. Nature (1987) 329:3017. Phase 1b Study of Safety, Tolerability and Efficacy of R1507, a Monoclonal Antibody to IGF-1R in Combination With Multiple Standard Oncology Regimens in Patients With Advanced Solid Malignancies. Dupont J, LeRoith D. Insulin and Insulin-Like Growth Factor I Receptors: Similarities and Differences in Signal Transduction. Acta Endocrinol (Copenh) (1988) 118:41521. Dawson TP, Radulescu A, Wynford-Thomas D. Expression of Mutant p21ras Induces Insulin-Like Growth Factor 1 Secretion in Thyroid Epithelial Cells. Further, Pritchard etal. GH and its primary downstream mediator, insulin-like growth factor I (IGF-I), play a critical role in formation, maintenance, and regeneration of skeletal muscles. As I will describe, IGF-IR plays not only a critical role in the pathogenesis of TAO, but can be effectively targeted as a therapeutic strategy for managing the disease. Hermani A, Shukla A, Medunjanin S, Werner H, Mayer D. Cell Signal. Teprotumumab for the treatment of active thyroid eye disease. Infusions administered every 3 weeks for 21 weeks eight infusions in total. Both insulin and IGF-I can regulate the rate of major histocompatibility complex class 1 (MHC class 1) gene transcription (40). Lee YJ, Park DJ, Shin CS, Park KS, Kim SY, Lee HK, et al. IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms. Thyroid (2012) 22:4306. Ligands including IGF-I, IGF-II, and insulin share important structural and functional relationships including the promiscuous utilization of multiple receptors, such as IGF-IR, IGF-IIR, and IR. Growth and Thyroid Function in Children Treated With Growth Hormone. Teprotumumab for the treatment of active thyroid eye disease. Several years after the initial observation of Tsui et al., -arrestin was found to function as a scaffold for both TSHR and IGF-IR (122), This association potentially accounts for protein:protein crosstalk as underlying the apparent importance of IGF-IR activity in TSHR signaling. Like the initial study, this trial was also placebo-controlled, double-masked, and all patients were clinically euthyroid, and were judged to manifest active, moderate to severe TAO. J Clin Endocrinol Metab (1993) 76:1199201. (114). It shares >60% homology with IGF-II and by 50% homology with proinsulin structures [ 1 ]. Douglas RS, Naik V, Hwang CJ, Afifiyan NF, Gianoukakis AG, Sand D, et al. doi: 10.1074/jbc.271.46.29400, 106. The N-domain contains 12 conserved cysteine residues and a hydrophobic patch important for IGF binding. The https:// ensures that you are connecting to the Ingbar and colleagues found that both IGF-IR- and IR- activating ligands could provoke proliferation and DNA synthesis in these cultured cells. These deficits have resulted historically in suboptimal medical management of both the thyroid dysfunction and TAO components of this vexing condition (113) (Figure 4). Bch TR, Biebermann H, Kalwa H, Pinkenburg O, Hager D, Barth H, et al. Others included improved CAS > 2 points, reduction in proptosis, both measured as independent variables from baseline, reduced diplopia 1 Gorman scale grade and mean change in the GO-QOL questionnaire score. Ruchala M, Skiba A, Gurgul E, Uruski P, Wasko R, Sowinski J. At postnatal day 14, mTOR-dependent epithelial cell proliferation and serum TSH were detectable. Advanced Semper Fit Course Flashcards | Quizlet These highly significant differences continued over the duration of the treatment phase (p<0.001 at all clinical assessments). doi: 10.1210/jcem-52-1-144, 6. doi: 10.1073/pnas.72.2.604, 69. Further, thyroid hormones and thyrotropin (TSH) can influence the biological effects of growth hormone and IGF-I on target tissues. Kushchayeva YS, Kushchayev SV, Startzell M, Cochran E, Auh S, Dai Y, et al. Insulin-like growth factor binding protein 5: Diverse roles in cancer. The mitogenic activities of both normal and acromegalic sera can be attenuated by pretreating them with neutralizing monoclonal anti-IGF-I antibodies. IGF-1 Receptor Deficiency in Thyrocytes Impairs Thyroid Hormone Secretion and Completely Inhibits TSH-Stimulated Goiter. doi: 10.1007/s11102-010-0224-9, 59. Patients with acromegaly are at increased risk for a variety of cancers besides those of the thyroid. McCune-Albright syndrome occurring in adults can be associated with toxic multinodular goiter and an increased risk of thyroid cancer (60). Three Endocrine Neoplasms: An Unusual Combination of Pheochromocytoma, Pituitary Adenoma, and Papillary Thyroid Carcinoma. Mechanisms of Insulin Action. Dominant role of microglial and macrophage innate immune - PubMed (D) Overall responder rate (percent of patients with 2-point reduction in CAS and 2 mm reduction in proptosis from baseline in study eye). eCollection 2020. (2005) 142:4452. With regard to Graves disease (GD) and the periocular process frequently associated with it, namely thyroid-associated ophthalmopathy (TAO), IGF-IR has been found overexpressed in orbital connective tissues, T and B cells in GD and TAO. In addition to their role in fetal and childhood growth . Cavaliere H, Knobel M, Medeiros-Neto G. Effect of Thyroid Hormone Therapy on Plasma Insulin-Like Growth Factor I Levels in Normal Subjects, Hypothyroid Patients and Endemic Cretins. Adapted from Worrall etal. Fukushima T, Nedachi T, Akizawa H, Akahori M, Hakuno F, Takahashi S. Distinct Modes of Activation of Phosphatidylinositol 3-Kinase in Response to Cyclic Adenosine 3, 5-Monophosphate or Insulin-Like Growth Factor I Play Different Roles in Regulation of Cyclin D1 and p27Kip1 in FRTL-5 Cells. However, several studies have shown an association between increased levels of circulating IGF-1 and the risk of developing solid malignancies, including PCa. Arufe MC, Lu M, Lin RY. In that study, T3 was shown to enhance IGF-1R signaling and its upregulation of PI3K/Akt/GSK-3 signaling. However, the roles of IGF-1 variants in mild traumatic brain injury (mTBI) are not yet fully understood. Qu X, Wu Z, Dong W, Zhang T, Wang L, Pang Z, et al. Their potential relevance to the thyroid has been reviewed recently in detail (8). The Effect of Altered Thyroid Status on Pituitary Hormone Messenger Ribonucleic Acid Concentrations in the Rat. They support the important roles played by each in the maintenance of both endocrine functions at multiple levels. doi: 10.21873/anticanres.13409, 47. While IGF-IR primarily functions as an integral membrane receptor the activation of which provokes tyrosine kinase autophosphorylation, recent studies have revealed the nuclear translocation of IGF-IR as well as other components of the IGF-I pathway (15). New Engl J Med (2016) 375:155265. Gianoukakis AG, Douglas RS, King CS, Cruikshank WW, Smith TJ. Growth Hormone Secretion and Plasma Somatomedin-C in Primary Hypothyroidism. doi: 10.1210/endo-119-2-940, 95. 12 Articles, This article is part of the Research Topic, Impact of GH and its Primary Effector, IGF-I, on the Thyroid Gland, Interplay Between IGF-I and Thyroid Hormone Metabolism and Pathways, Impact of Thyroidal Status on the GH/IGF-I Axis, IGF-I and Insulin Enhance the Actions of TSH and Thyroid-Stimulating Immunoglobulins: Evidence for Interplaying Pathways, Emerging Relevance of IGF-IR in the Pathogenesis of GD and TAO, Culmination of Evidence That IGF-IR Represents A Clinically Important Therapeutic Target in TAO, Teprotumumab Becomes First Ever FDA-Approved Medical Therapy for TAO. The enhancement of GH synthesis by T3 is mediated through enhanced gene transcription while the inhibition by IGF-I of GH induction appears to reflect changes in posttranscriptional events. Synergistic roles of IgM and complement in antigen trapping and Interaction of TSH, Insulin and Insulin-Like Growth Factors in Regulating Thyroid Growth and Function. Among the six distinct types of IGFBPs, IGFBP-5 is the most highly conserved across species and has the broadest range of biological activities. Based on those findings, the development of teprotumumab, a -arrestin biased agonist as a therapeutic has resulted in the first medication approved by the US FDA for the treatment of TAO. It is however, difficult to distinguish effects by locally produced IGF-1 compared to liver-derived IGF-1 appearing in the circulation. In those studies, IGF-I transcript was undetectable in the absence of TSH, effects that were mimicked by forskolin. Girnita L, Shenoy SK, Sehat B, Vasilcanu R, Girnita A, Lefkowitz RJ, et al. 2007 May;148(5):2138-47. doi: 10.1210/en.2006-0041. 382; 341-352. Clin Cancer Res: An Off J Am Assoc Cancer Res (2010) 16:245865. doi: 10.1210/endo.138.3.5018, 88. J Clin Endocrinol Metab (2009) 94:194550. Oncol Rep (2012) 27:86772. eCollection 2022. Wster C, Steger G, Schmelzle A, Gottswinter J, Minne HW, Ziegler R. Increased Incidence of Euthyroid and Hyperthyroid Goiters Independently of Thyrotropin in Patients With Acromegaly. The drug safety profile from that trial was encouraging (123). Solomon J, Greep RO. IGF-IIR (mannose-6-phosphate receptor) influences IGF-II degradation and participates in the biology of the Golgi apparatus. Int Rev Cytol. Among these, IGFs impact the thyroid and the hormones that it generates. In the absence of TSH, it appears that GH has little or no effect on thyroid size (52). Arch Ophthal (In Press) (2020) 2447 doi: 10.1001/jamaophthalmol.2020.5296, 132. Mediating the actions of insulin and IGF-I are their respective, closely related receptors (IGF-IR and IR, respectively), both belonging to the tyrosine kinase family (Figure 2). Insulin-like growth factor - Wikipedia The initial (partial) dose (10 mg/Kg B.W.) JAAD Case Rep (2020) 12812 doi: 10.1016/j.jdcr.2020.09.003, 133. These effects are similar to those of TSH in FRTL-5 cells. Cells (2020) 9. doi: 10.3390/cells9040862, 122. At analysis it was discovered that an imbalance of smokers occurred with more representation of tobacco users in the placebo group. Ohlsson C, Nilsson A, Isaksson O, Bentham J, Lindahl A. Malaguarnera R, Frasca F, Garozzo A, Gian F, Pandini G, Vella V, et al. doi: 10.1007/s11154-007-9063-z. The most common adverse events were muscle cramping and hyperglycemia, most commonly seen in patients with baseline abnormalities in glycemic control or frank diabetes mellitus. The phase 3 trial included an extension where all non-responders were offered teprotumumab as an open label, regardless of whether or not they had received the active drug or placebo during the 24-week treatment phase. Zebrafish IGFBP-5a and the conserved zinc metalloproteinase Papp-aa are expressed in ionocytes. doi: 10.1002/jbmr.5, 70. . The effect of insulin-like growth factor 1 on the recovery of facial doi: 10.18632/oncotarget.15704, 127. Development of a Disease Specific Quality of Life Questionnaire for Patients With Graves Ophthalmopathy: The GO-QOL. In their very recent report, Natchev and colleagues studied a cross-section of 146 acromegalic patients and found that secondary hypothyroidism and hyperthyroidism are commonly encountered (48). Teprotumumab For Optic Neuropathy in Thyroid Eye Disease. Childhood deficiency of GH can occur as an isolated defect, whereas those occurring in adults are typically associated with a constellation of pituitary-hypothalamic insufficiencies and are mostly associated with anatomic lesions. Received: 14 January 2021; Accepted: 20 April 2021;Published: 04 June 2021. Phosphatidylinositol 3-Kinase/Nuclear Factor-Kappa B Signaling Pathway is Involved in the Regulation of IGF-I on Fas-Associated Death Domain-Like interleukin-1-Converting Enzyme-Inhibitory Protein Expression in Cultured FRTL Thyroid Cells. (C) Coronal, contrast-enhanced, fat-saturated, T1-weighted MRIs in a single patient receiving teprotumumab at baseline and at week 24. J. Med, Smith T.J. and Hegedus L., Graves Disease, 375; 1552-1565. Orbital fibroblasts exhibit particularly robust responses to inflammatory mediators. Endocrinology (1997) 138:1194203. Proc Natl Acad Sci USA (1978) 75:459. Corrigendum: Insulin-Like Growth Factor Binding Protein-5 in Physiology and Disease. Endocrinology (1990) 126:5504. The insulin-like growth factor system: A target for endocrine Insulin-like growth factor receptor signaling in tumorigenesis and drug -arrestin activates kinase desensitization and ubiquitination and initiates kinase-independent signaling through MAPK. Sisson JC, Giordano TJ, Avram AM. Pharmacol Rev (2010) 62:199236. Jones JI, Clemmons DR. Insulin-Like Growth Factors and Their Binding Proteins: Biological Actions. Propylthiouracil treatment in rats results in substantially increased IGF-II binding site density on thyroid epithelial cells (84). Serum IGFBP3 and IGFBP4 levels are reduced in hypothyroid animals (82). Blethen SL, White NH, Santiago JV, Daughaday WH. Insulin-Like Growth Factor II Receptor as a Multifunctional Binding Protein. Exogenous GH administration in GH-deficient children has been shown to reduce circulating levels of T4, although the mechanism(s) involved has yet to be established. These include those of the colon, prostate, and breast, but thyroid cancers may be the most common malignancy associated with the disease (58). (E) Diplopia response (percent of patients with improvement of at least 1 grade from baseline). Baseline proptosis (both eyes 24mm), edema, upper and lower eyelid retraction, and multiple inflammatory signs (CAS 5 bilaterally). Insulin and thyroid hormones can act synergistically by mutual enhancement. Thelen MH, Muller A, Zuidwijk MJ, van der Linden GC, Simonides WS, van Hardeveld C. Differential Regulation of the Expression of Fast-Type Sarcoplasmic-Reticulum Ca(2+)-ATPase by Thyroid Hormone and Insulin-Like Growth Factor-I in the L6 Muscle Cell Line. J Endocrinol. In the bloodstream and in local tissues, most IGF molecules are bound by one of the members of the IGF-binding protein (IGFBP) family, of which six distinct types exist. This chapter summarizes literature related to how expression of IGF-1 and its signaling components are altered after traumatic brain injury (TBI). IGF-I is required for normal embryonic growth in mice. Endocr Rev (2019) 40:23667. Further, these changes reverted to baseline following completion of the treatment phase of the trial. Terwee CB, Gerding MN, Dekker FW, Prummel MF, Wiersinga WM. Methods Based . The failure of teprotumumab in the cancer space had made it available for potential repurposing in TAO. In contrast, thyroid hormones induce IGF-IR mRNA expression in rat epiphyseal chondrocytes (85) and enhance IGF-I binding in rat pituitary cells (86). Note marked enhancement of the inferior rectus muscle (white arrowhead) and orbital fat (white arrow) as well as inferior rectus muscle enlargement. Background Insulin-like growth factor 1 (IGF-1) is an important pleiotropic hormone that exerts neuroprotective and neuroreparative effects after a brain injury. Mechanisms of action of intravenous immunoglobulin - PubMed This phenomenon may result from enhanced thyroid sensitivity to the actions of TSH caused by either growth hormone, IGF-I, or both.
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