Lessons Learned from Targeting IGF-I Receptor in Thyroid-Associated Ophthalmopathy

Janssen, Joseph A M J L; Smith, Terry J.

doi:10.3390/cells10020383

Cited by 15 publications

(13 citation statements)

References 109 publications

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“…Historical models of GD and TAO have focused almost entirely on autoimmune reactivity directed against the TSH receptor. Emerging is the theory that IGF-1R is a second participating antigen in TAO by virtue of its interactions with IGFs and anti–IGF-1R antibodies generated in GD 6 . Strong evidence supports IGF-1R in the pathogenesis of TAO, which has opened a pathway for new drug therapy development specifically for TED 7 …”

Section: Pathophysiologymentioning

confidence: 99%

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Teprotumumab, a Human Monoclonal Antibody Insulin-like Growth Factor-1 Receptor Inhibitor for Thyroid Eye Disease

O’Malley¹

2022

Clin Nurse Spec

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raves' ophthalmopathy (GO) is an auto-inflammatory disease associated with Graves' disease (GD). 1 Also called thyroid-associated orbitopathy (TAO), both are members of the emerging acronym in the literature called thyroid eye disease or TED. 1,2 Greater than 90% of patients with Graves' orbitopathy have GD, a complex inflammatory autoimmune condition caused by thyrotropin (TSH) receptor autoantibodies. 3 Graves' disease is common throughout the world. Women in their third to fifth decade are primarily affected with an overall prevalence of 0.5%. Approximately 15% of patients with GD who do not present with GO at baseline will typically develop it within 3 to 6 months. 3 Eyelid retraction, restrictive strabismus, proptosis, exposure keratopathy, and optic neuropathy of TAO most often present with Graves' hyperthyroidism. 4 Persons also experience disabling vision effects and facial disfigurement, which has a significant negative impact on quality of life and mental health. 3,5 Only 3% to 5% of patients will progress to severe disease involving ulceration of the cornea, vision-threatening optic neuropathy, and cornea decompensation. 2 For most patients, predisease orbital anatomy will not be restored, and for some, surgery will be required to reduce disfigurement and restore vision. Since the 1960s, immunosuppression with steroids has been the primary medication therapy during active disease. 5

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Section: Pathophysiologymentioning

confidence: 99%

“…Emerging evidence suggests that teprotumumab may be effective for both compressive optic neuropathy and chronic, stable TAO and for pretibial myxedema. As for aggressive TAO and that which has become clinically stable, teprotumumab may prove to be therapeutically beneficial 6,8,9 …”

Section: Therapymentioning

confidence: 99%

Teprotumumab, a Human Monoclonal Antibody Insulin-like Growth Factor-1 Receptor Inhibitor for Thyroid Eye Disease

O’Malley¹

2022

Clin Nurse Spec

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“…[ 19 20 21 ] Initial research was focused principally on the role of the TSHR in TED. [ 22 ] Although increased expression of the TSHR has been found on orbital fibroblasts of patients with active TED,[ 23 ] a direct causal relationship between the TSHR increase and the pathophysiology was not clear. Further research disclosed that the IGF-1R colocalizes with TSHR in human orbital fibroblasts, forming a physical and functional signaling complex, and leads to the up-regulation of genes in the IGF/IGF-1R signaling pathway.…”

Section: Pathophysiology Of Tedmentioning

confidence: 99%

“…Promising initial data from patients treated with teprotumumab (Horizon Therapeutics, Dublin, IRL), a human monoclonal antibody that binds to IGF-1R with high affinity and specificity, supports the idea that IGF-1R plays a central role in the pathogenesis of TED. [ 22 34 35 ]…”

Section: Pathophysiology Of Tedmentioning

confidence: 99%

Update on thyroid eye disease: Regional variations in prevalence, diagnosis, and management

Ford

Wester

et al. 2022

Indian Journal of Ophthalmology

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Thyroid eye disease (TED) is a rare disease that can lead to decreased quality of life, permanent disfigurement, and vision loss. Clinically, TED presents with exophthalmos, periorbital edema, extraocular muscle dysfunction, and eyelid retraction, and can lead to vision-threatening complications such as exposure to keratopathy and dysthyroid optic neuropathy (DON). Over the last several years, significant advancements have been made in the understanding of its pathophysiology as well as optimal management. Ethnic variations in the prevalence, clinical presentation, and risk of vision-threatening complications of TED are summarized, and risk factors associated with TED are discussed. Additionally, significant advances have been made in the management of TED. The management of TED traditionally included anti-inflammatory medications, orbital radiation therapy, orbital surgical decompression, and biologic therapies. Most recently, targeted therapies such as teprotumumab, an insulin-like growth factor-1 receptor antagonist, have been studied in the context of TED, with promising initial data. In this review, updates in the understanding and management of TED are presented with a focus on the international variations in presentation and management.

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“…Orbital fibroblasts express thyroid-stimulating hormone receptors (TSHRs) on their surface and are activated by TSHR autoantibody stimulation, which contributes to the expansion and remodeling of the orbital soft tissues (3). Several investigators have also reported that GO orbital fibroblasts highly express the insulin-like growth factor 1 receptor (IGF-1R) that may act in concert with the TSHR (4)(5)(6). Moreover, GO orbital fibroblasts can be activated by locally produced platelet-derived growth factor-BB (PDGF-BB) that stimulates proliferation, adipogenesis, cytokine and extracellular matrix production, as well as enhanced TSHR expression (7).…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase 4 Controls Extracellular Matrix Production in Orbital Fibroblasts from Graves' Ophthalmopathy Patients

Ekronarongchai

Palaga

Saonanon

et al. 2021

Thyroid

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Background: Graves' ophthalmopathy (GO) is an autoimmune eye disease with the characteristic symptoms of eyelid retraction and proptosis. Orbital fibroblast activation induced by platelet-derived growth factor-BB (PDGF-BB) stimulation plays a crucial role in GO pathogenesis, leading to excessive proliferation and extracellular matrix production by orbital fibroblasts. Currently, GO treatment options remain limited and novel therapies including targeted drugs are needed. Histone deacetylases (HDACs) are associated with the development and progression of several cancers and autoimmune diseases by epigenetically controlling gene transcription, and HDAC inhibitors (HDACis) may have therapeutic potential. Nevertheless, the role of HDACs in orbital fibroblasts from GO is unknown. Therefore, we studied the expression of HDACs as well as their contribution to extracellular matrix production in orbital fibroblasts. Methods: Orbital tissues were obtained from GO patients (n = 18) who underwent decompression surgery with approval from the Institutional Review Board of the Faculty of Medicine (Protocol number 401/61), Chulalongkorn University (Bangkok, Thailand). Furthermore, orbital tissue was obtained from control patients (n = 3) without inflammatory or thyroid disease who underwent surgery for cosmetic reasons. Orbital fibroblast cultures were established from the orbital tissues. HDAC mRNA and protein expression in orbital fibroblasts was analyzed by reverse transcription-quantitative real-time PCR and Western blot. PDGF-BB-activated orbital fibroblast and orbital tissues were treated with HDACis or HDAC4 small-interfering RNA. Results: PDGF-BB-stimulated orbital fibroblasts had upregulated HDAC4 mRNA and protein expression. HDAC4 mRNA expression was significantly higher in GO compared with healthy control orbital fibroblasts. Histone H3 lysine 9 acetylation (H3K9ac) decreased upon PDGF-BB stimulation. Treatment with HDAC4i (tasquinimod) and HDAC4/5i (LMK-235) significantly decreased both proliferation and hyaluronan production in PDGF-BB-stimulated orbital fibroblasts. HDAC4 silencing reduced mRNA expression of hyaluronan synthase 2 (HAS2), collagen type I alpha 1 chain (COL1A1), Ki67, and a-smooth muscle actin (a-SMA), as well as hyaluronan production in PDGF-BB-stimulated orbital fibroblasts. Tasquinimod significantly reduced HAS2 and a-SMA mRNA expression in whole orbital tissue. Conclusion: Our data indicated, for the first time, that altered HDAC4 regulation along with H3K9 hypoacetylation might represent a mechanism that contributes to excessive proliferation and extracellular matrix production by orbital fibroblasts in GO. HDAC4 might represent a novel target for GO therapy.

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Lessons Learned from Targeting IGF-I Receptor in Thyroid-Associated Ophthalmopathy

Cited by 15 publications

References 109 publications

Teprotumumab, a Human Monoclonal Antibody Insulin-like Growth Factor-1 Receptor Inhibitor for Thyroid Eye Disease

Teprotumumab, a Human Monoclonal Antibody Insulin-like Growth Factor-1 Receptor Inhibitor for Thyroid Eye Disease

Update on thyroid eye disease: Regional variations in prevalence, diagnosis, and management

Histone Deacetylase 4 Controls Extracellular Matrix Production in Orbital Fibroblasts from Graves' Ophthalmopathy Patients

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