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.

The activation and proliferation of human Tenon's fibroblasts (HTFs) play a vital role in the fibrosis in the pathology of the scar formation after the glaucoma filtration surgery. Transforming growth factor β1 (TGFβ1)/Smads signaling has been reported to promote fibrosis. In our previous study, we revealed that TGFβ1‐induced orbital fibroblast activation and proliferation through Wnt/β‐catenin signaling. As microRNA (miR)‐139 could target several factors in Wnt signaling to modulate fibrosis, here, the effect and mechanism of miR‐139 in HTF activation and proliferation were investigated. miR‐139 overexpression significantly reversed the TGFβ1‐induced increase in collagen I and α‐smooth muscle actin contents and proliferation in HTFs. CTNNB1 and CTNND1 were direct downstream of miR‐139 and can significantly restore the suppressive effect of miR‐139 on the activation and proliferation in HTFs under TGFβ1 stimulation. Smad2/3/4 complex inhibits the transcription activity of miR‐139, most possibly by Smad4 binding to the miR‐139 promoter. Taken together, we demonstrated a new mechanism of HTF activation and proliferation from the perspective of miRNA regulation, which may provide new strategies for improving the fibrosis after the glaucoma filtration surgery.

Thyroid-associated ophthalmopathy (TAO) is an autoimmune disease. Recent studies have found the aberrant epigenetics in TAO, including DNA methylation, non-coding RNAs, and histone modification. Many genes have an aberrant level of methylation in TAO. For example, higher levels are found in CD14, MBP, ANGLE1, LYAR and lower levels in DRD4 and BOLL. Non-coding RNAs are involved in the immune response (miR-146a, miR-155, miR-96, miR-183), fibrosis regulation (miR-146a, miR-21, miR-29), adipogenesis (miR-27) and are thought to play roles in TAO. MicroRNA is also related to the clinical activity score (miR-Let7d-5p) and may be a predictor of glucocorticoid therapy (miR-224-5p). The quantities of H4 in TAO are increased compared with euthyroid control subjects, and the role of histone modifications in Graves’ disease may lead to better understanding of its role in TAO. More studies are needed to explain the role of epigenetics in TAO and provide potential therapeutic strategies.

Background Research on Graves ophthalmopathy has increased remarkably over the last 2 decades; however, few statistical analyses of the data presented in these publications have been conducted. Objective This study aims to detect and analyze emerging trends and collaboration networks in Graves ophthalmopathy research. Methods Graves ophthalmopathy–related publications from 1999 to 2019 were collected from the Web of Science Core Collection Database. Collected publications were restricted by category (article or review) and language (English). Bibliometric analyses included changes in the annual numbers of publications, journals, authors, countries, institutions, keywords, and references. Results In total, 3051 publications that met the criteria were collected. The number of annual publications has exhibited an increasing trend over the last 20 years. The journal Thyroid ranked first, publishing 183 Graves ophthalmopathy–related studies. There was no evidence of a relationship between impact factor (IF) and the number of publications (P=.69). The author Smith TJ had the largest number of publications on Graves ophthalmopathy (n=83). Of the countries that had published Graves ophthalmopathy–related articles, the United States had the largest number (n=784) and the highest centrality (0.18). Among institutions, the University of Pisa (Italy) contributed the most Graves ophthalmopathy–related articles (n=114). The most recent burst keywords (proliferation, rituximab, and selenium) and references may provide clues on emerging trends in research and clinical practice. Conclusions This bibliometric analysis highlights countries, institutions, and authors who contributed to Graves ophthalmopathy–related publications. Emerging trends in Graves ophthalmopathy research, based on burst keywords and references, may provide clues relevant to clinical practice and future research.

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BACKGROUND Research on Graves’ ophthalmopathy(GO) increased remarkably in recent two decades, however, few studies provided statistical analysis to these publications. OBJECTIVE The purpose of this study is to detect and analyze the emerging trend and collaboration networks on GO. METHODS GO-related publications were collected from 1999 to 2019 from the Web of Science Core Collection Database. The publications were collected after restricting the publications with the category of article or review and language of English. The content of bibliometric analysis included changes in the annual number of publications, journals, authors, countries and institutions, keywords, and references. RESULTS There were 3051 publications collected which met the criterion. The number of annual publications had an increasing trend over the last 20 years. THYROID published 183 assays in total related to GO and ranked first. SMITH TJ had the largest number of publications on GO(83). The United States had the largest number of articles(784) and highest centrality(0.18) among the countries that had published essays related to GO. The UNIV PISA, which belonged to Italy, contributed 114 articles that are ahead of other institutions on the number of articles related to GO. The most recent burst keywords (proliferation, rituximab, and selenium) and references may provide clues on an emerging trend of research and clinical decision. CONCLUSIONS This bibliometric analysis highlight countries, institutions, and authors which contributed to the publications on GO. And the possible emerging trends on GO research extracted from burst keywords and references may provided the clues on clinical decision making and future research.