scholarly journals Ganglioside GT1b increases hyaluronic acid synthase 2 via PI3K activation with TLR2 dependence in orbital fibroblasts from thyroid eye disease patients

BMB Reports ◽  
2021 ◽  
Vol 54 (2) ◽  
pp. 136-141
Author(s):  
Hyun Kyu Yoo ◽  
Hyunju Park ◽  
Hye Suk Hwang ◽  
Hee Ja Kim ◽  
Youn-Hee Choi ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Thyroid Eye Disease ◽  
Eye Disease ◽  
Hyaluronic Acid Synthase ◽  
Pi3k Activation ◽  
Orbital Fibroblasts ◽  
Ganglioside Gt1b

Inhibition of TSH/IGF-1 receptor crosstalk by Teprotumumab as a treatment modality of Thyroid Eye Disease

2021 ◽  
Author(s):  
Christine C Krieger ◽  
Xiangliang Sui ◽  
George J Kahaly ◽  
Susanne Neumann ◽  
Marvin C Gershengorn
Keyword(s):  
Dose Response ◽  
Treatment Modality ◽  
Thyroid Eye Disease ◽  
Tsh Receptor ◽  
Eye Disease ◽  
Receptor Crosstalk ◽  
Orbital Fibroblast ◽  
Orbital Fibroblasts ◽  
Biphasic Dose Response

Abstract Context We previously presented evidence that TSH receptor (TSHR)-stimulating autoantibodies (TSAbs) bind to and activate TSHRs but do not bind to IGF1 receptors (IGF1Rs). Nevertheless, we showed that IGF1Rs were involved in thyroid eye disease (TED) pathogenesis because TSAbs activated crosstalk between TSHR and IGF1R. Teprotumumab, originally generated to inhibit IGF1 binding to IGF1R, was recently approved for the treatment of TED (Tepezza®). Objective To investigate the role of TSHR/IGF1R crosstalk in teprotumumab treatment of TED. Design We used orbital fibroblasts from patients with TED (TEDOFs) and measured stimulated hyaluronan (HA) secretion as a measure of orbital fibroblast activation by TED immunoglobulins (TED-Igs) and monoclonal TSAb M22. We previously showed that M22, which does not bind to IGF1R, stimulated HA in a biphasic dose-response with the higher-potency phase dependent on TSHR/IGF1R crosstalk and the lower-potency phase independent of IGF1R. Stimulation by TED-Igs and M22 was measured in the absence or presence of Teprotumumab Biosimilar (Tepro) or K1-70, an antibody that inhibits TSHR. Results We show: 1) Tepro dose-dependently inhibits stimulation by TED-Igs; 2) Tepro does not bind to TSHRs; 3) Tepro inhibits IGF1R-dependent M22-induced HA production, which is mediated by TSHR/IGF1R crosstalk, but not IGF1R-independent M22 stimulation; and 4) β-arrestin 1 knockdown, which blocks TSHR/IGF1R crosstalk, prevents Tepro inhibition of HA production by M22 and by a pool of TED-Igs. Conclusion We conclude that Tepro inhibits HA production by TEDOFs by inhibiting TSHR/IGF1R crosstalk and suggest that inhibition of TSHR/IGF1R crosstalk is the mechanism of its action in treating TED.

LncRNA LPAL2/miR-1287-5p/EGFR axis modulates TED derived orbital fibroblast activation through cell adhesion factors

2021 ◽  
Author(s):  
Nuo Wang ◽  
Shi-ying Hou ◽  
Xin Qi ◽  
Mi Deng ◽  
Jia-min Cao ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Akt Signaling ◽  
Thyroid Eye Disease ◽  
Differentially Expressed ◽  
Eye Disease ◽  
Fibroblast Activation ◽  
Orbital Fibroblast ◽  
Orbital Fibroblasts ◽  
Adhesion Factor ◽  
Tgf Β1

Abstract Background and aims The activation of orbital fibroblasts, the prime targets in thyroid eye disease, is central to its underlying pathogenesis. We aimed to investigate the mechanism of thyroid eye disease orbital fibroblast activation from the perspective of non-coding RNA regulation. Methods Immunofluorescence (IF) staining was applied to evaluate the fibrotic changes in target cells. Cell proliferation were evaluated by EDU and colony formation assays. Collagen I concentration was determined by ELISA assay. Human microarray analysis was performed on three thyroid eye disease and 3 healthy control orbital tissue samples. Results Bioinformatics analysis showed that cell adhesion signaling factors were differentially expressed in thyroid eye disease tissues, including I-CAM-1, I-CAM-4, V-CAM, and CD44, which were all upregulated in diseased orbital tissues. LncRNA LPAL2 level was also upregulated in orbital tissues and positively correlated with I-CAM-1 and I-CAM-4 expression. Stimulation of the thyroid eye disease orbital fibroblasts by TGF-β1 significantly increased the expression of I-CAM-1, I-CAM-4, and LPAL2. Knockdown of LPAL2 in orbital fibroblasts inhibited TGF-β1-induced increases in cell adhesion factor levels and orbital fibroblast activation. Microarray profiling was performed on thyroid eye disease and normal orbital tissues to identify differentially expressed miRNAs and miR-1287-5p was remarkably reduced within diseased orbital samples. miR-1287-5p was directly bound to EGFR 3’UTR and LPAL2 and LPAL2 modulated EGFR/AKT signaling through targeting miR-1287-5p. Conclusions The LPAL2/miR-1287-5p axis modulated TGF-β1-induced increases in cell adhesion factor levels and thyroid eye disease orbital fibroblast activation through EGFR/AKT signaling.

Hyaluronic Acid Gel Injection for Upper Eyelid Retraction in Thyroid Eye Disease

2014 ◽  
Vol 30 (5) ◽  
pp. 400-404 ◽  
Author(s):  
Jocelyne C. Kohn ◽  
Daniel B. Rootman ◽  
Wenjing Liu ◽  
Alice S. Goh ◽  
Catherine J. Hwang ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Thyroid Eye Disease ◽  
Eye Disease ◽  
Eyelid Retraction ◽  
Upper Eyelid ◽  
Upper Eyelid Retraction ◽  
Gel Injection ◽  
Acid Gel ◽  
Hyaluronic Acid Gel

scholarly journals Targeting TSH and IGF-1 Receptors to Treat Thyroid Eye Disease

2020 ◽  
Vol 9 (Suppl. 1) ◽  
pp. 59-65
Author(s):  
Susanne Neumann ◽  
Christine C. Krieger ◽  
Marvin C. Gershengorn
Keyword(s):  
Thyroid Stimulating Hormone ◽  
Thyroid Eye Disease ◽  
Therapeutic Interventions ◽  
Eye Disease ◽  
Thyroid Cells ◽  
Hormone Synthesis ◽  
Dependent Component ◽  
Graves Orbitopathy ◽  
Blocking Antibodies ◽  
Orbital Fibroblasts

Graves’ disease (GD) is an autoimmune disease caused in part by thyroid-stimulating antibodies (TSAbs) that activate the thyroid-stimulating hormone receptor (TSHR). In Graves’ hyperthyroidism (GH), TSAbs cause persistent stimulation of thyroid cells leading to continuous thyroid hormone synthesis and secretion. Thyroid eye disease (TED), also called Graves’ orbitopathy, is an orbital manifestation of GD. We review the important roles of the TSHR and the insulin-like growth factor 1 receptor (IGF-1R) in the pathogenesis of TED and discuss a model of TSHR/IGF-1R crosstalk that considers two pathways initiated by TSAb activation of TSHR in the eye, an IGF-1R-independent and an IGF-1R-dependent signaling pathway leading to hyaluronan (HA) secretion in orbital fibroblasts. We discuss current and future therapeutic approaches targeting the IGF-1R and TSHR. Teprotumumab, a human monoclonal anti-IGF-1R-blocking antibody, has been approved as an effective treatment in patients with TED. However, as the TSHR seems to be the primary target for TSAbs in patients with GD, future therapeutic interventions directly targeting the TSHR, e.g. blocking antibodies and small molecule antagonists, are being developed and have the advantage to inhibit the IGF-1R-independent as well as the IGF-1R-dependent component of TSAb-induced HA secretion. Antigen-specific immunotherapies using TSHR peptides to reduce serum TSHR antibodies are being developed also. These TSHR-targeted strategies also have the potential to treat both GH and TED with the same drug. We propose that combination therapy targeting TSHR and IGF-1R may be an effective and better tolerated treatment strategy for TED.

scholarly journals Orbital Fibroblasts From Thyroid Eye Disease Patients Differ in Proliferative and Adipogenic Responses Depending on Disease Subtype

2013 ◽  
Vol 54 (12) ◽  
pp. 7370 ◽  
Author(s):  
Ajay E. Kuriyan ◽  
Collynn F. Woeller ◽  
Charles W. O'Loughlin ◽  
Richard P. Phipps ◽  
Steven E. Feldon
Keyword(s):  
Thyroid Eye Disease ◽  
Eye Disease ◽  
Disease Subtype ◽  
Orbital Fibroblasts

scholarly journals Therapeutic Effect of α-MSH in Primary Cultured Orbital Fibroblasts Obtained from Patients with Thyroid Eye Disease

2021 ◽  
Vol 22 (20) ◽  
pp. 11225
Author(s):  
Pei-Wen Cheng ◽  
Pei-Jhen Tsai ◽  
Ming-Hong Tai ◽  
Youn-Shen Bee
Keyword(s):  
Therapeutic Effect ◽  
Primary Cultures ◽  
Sepsis Syndrome ◽  
Thyroid Eye Disease ◽  
Control Treatment ◽  
Eye Disease ◽  
Protein Levels ◽  
Dependent Inhibition ◽  
Orbital Fibroblasts

Inflammation, hyaluronan production, and adipogenesis are the main pathological events leading to thyroid eye disease (TED). α-Melanocytemelanocyte-stimulating hormone (α-MSH) is a well-known tridecapeptidetreatment for several inflammatory disorders including sepsis syndrome, acute respiratory distress syndrome, rheumatoid arthritis, and encephalitis. Here, we investigated the effect of α-MSH treatment on TED. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and Lactate Dehydrogenase (LDH) assays were performed to analyze the effect of α-MSH on cell viability and it’s toxicity. Using primary cultures of orbital fibroblasts from TED patients and non-TED as control, we examined the effects of α-MSH on proinflammatory cytokine production induced by interleukin (IL)-1β, further analyzed by real-time reverse transcription-polymerase chain reaction (qPCR) and western blotting. Immunofluorescence staining assay and qPCR were performed to examine proopiomelanocortin (POMC) expression, the upstream neuropeptide of α-MSH in TED patients and non-TED control. Treatment with non-cytotoxic concentrations of α-MSH resulted in the dose-dependent inhibition of mRNA and protein levels (p < 0.05) for IL-1β-induced inflammatory cytokines: IL-6, IL-8, MCP-1, ICAM-1, and COX-2. The expression of POMC mRNA and protein were significantly higher in TED patients compared to non-TED control (p < 0.05). Our data show significant inhibitory effects of α-MSH on inflammation, POMC production in orbital fibroblasts. At present, this is the first in vitro preclinical evidence of α-MSH therapeutic effect on TED. These findings indicate that POMC and α-MSH may play a role in the immune regulation of TED and can be a potential therapeutic target.

scholarly journals Regulation of Lymphocyte Function by PPARγ: Relevance to Thyroid Eye Disease-Related Inflammation

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-12 ◽  
Author(s):  
G. M. Lehmann ◽  
T. M. Garcia-Bates ◽  
T. J. Smith ◽  
S. E. Feldon ◽  
R. P. Phipps
Keyword(s):  
Disease Progression ◽  
Thyroid Eye Disease ◽  
Eye Disease ◽  
Peroxisome Proliferator ◽  
Lymphocyte Function ◽  
Peroxisome Proliferator Activated Receptor ◽  
Orbital Tissue ◽  
Autoimmune Condition ◽  
Tissue Characteristics ◽  
Orbital Fibroblasts

Thyroid eye disease (TED) is an autoimmune condition in which intense inflammation leads to orbital tissue remodeling, including the accumulation of extracellular macromolecules and fat. Disease progression depends upon interactions between lymphocytes and orbital fibroblasts. These cells engage in a cycle of reciprocal activation which produces the tissue characteristics of TED. Peroxisome proliferator-activated receptor-γ(PPARγ) may play divergent roles in this process, both attenuating and promoting disease progression. PPARγhas anti-inflammatory activity, suggesting that it could interrupt intercellular communication. However, PPARγactivation is also critical to adipogenesis, making it a potential culprit in the pathological fat accumulation associated with TED. This review explores the role of PPARγin TED, as it pertains to crosstalk between lymphocytes and fibroblasts and the development of therapeutics targeting cell-cell interactions mediated through this signaling pathway.

scholarly journals Tear-Derived Exosome Proteins Are Increased in Patients with Thyroid Eye Disease

2021 ◽  
Vol 22 (3) ◽  
pp. 1115
Author(s):  
Jeong-Sun Han ◽  
Sung Eun Kim ◽  
Jun-Qing Jin ◽  
Na Ri Park ◽  
Ji-Young Lee ◽  
...  
Keyword(s):  
Thyroid Eye Disease ◽  
Eye Disease ◽  
Intercellular Signaling ◽  
Monocyte Chemoattractant Protein 1 ◽  
Reactive Protein ◽  
Control Subjects ◽  
Specific Proteins ◽  
Vascular Adhesion ◽  
And Control ◽  
Orbital Fibroblasts

Exosomes contain proteins, lipids, RNA, and DNA that mediate intercellular signaling. Exosomes can contribute to the pathological processes of various diseases, although their roles in ocular diseases are unclear. We aimed to isolate exosomes from tear fluids (TF) of patients with Thyroid eye disease (TED) and analyze the exosomal proteins. TFs were collected from eight patients with TED and eight control subjects. The number of TF exosomes were measured using nanoparticle-tracking analysis. The expression of specific proteins in the purified exosome pellets were analyzed using a Proteome Profiler Array Kit. Cultured normal orbital fibroblasts were incubated with TF exosomes from patients with TED and control subjects, and changes in inflammatory cytokine levels were compared. TF exosomes from TED patients showed more exosomes than the control subjects. The expression levels of exosomal proteins vitamin D-binding (VDB) protein, C-reactive protein (CRP), chitinase 3-like 1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), and vascular adhesion molecule-1 (VCAM-1) were significantly increased in patients with TED, compared to those of controls. Orbital fibroblasts exposed to TF exosomes from patients with TED showed significantly higher levels of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) production than those treated with control TF exosomes. Specific proteins showed higher expression in exosomes from TED patients, implying that they may play keys roles in TED pathogenesis.

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