Enrichment of IGF-1R and PPARγ signalling pathways in orbital inflammatory diseases: steps toward understanding pathogenesis.

Autor:	Verma R; Oculofacial Plastic and Reconstructive Surgery, Oregon Health & Science University Casey Eye Institute, Portland, Oregon, USA.; Casey Eye Institute, Oregon Health & Science University Casey Eye Institute, Portland, Oregon, USA., Choi D; Casey Eye Institute, Oregon Health & Science University Casey Eye Institute, Portland, Oregon, USA.; OHSU-PSU School of Public Health, Oregon Health & Science University, Portland, Oregon, USA.; Graduate School of Dentistry, Kyung Hee University, Seoul, South Korea.; Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA., Chen AJ; Oculofacial Plastic and Reconstructive Surgery, University of California San Diego- Shiley Eye Institute and Viterbi Family Department of Ophthalmology, La Jolla, California, USA., Harrington CA; Integrated Genomics Laboratory, Oregon Health & Science University, Portland, Oregon, USA., Wilson DJ; Casey Eye Institute, Oregon Health & Science University Casey Eye Institute, Portland, Oregon, USA., Grossniklaus HE; Emory Eye Center, Emory University, Atlanta, Georgia, USA., Dailey RA; Oculofacial Plastic and Reconstructive Surgery, Oregon Health & Science University Casey Eye Institute, Portland, Oregon, USA.; Casey Eye Institute, Oregon Health & Science University Casey Eye Institute, Portland, Oregon, USA., Ng J; Oculofacial Plastic and Reconstructive Surgery, Oregon Health & Science University Casey Eye Institute, Portland, Oregon, USA.; Casey Eye Institute, Oregon Health & Science University Casey Eye Institute, Portland, Oregon, USA., Steele EA; Oculofacial Plastic and Reconstructive Surgery, Oregon Health & Science University Casey Eye Institute, Portland, Oregon, USA.; Casey Eye Institute, Oregon Health & Science University Casey Eye Institute, Portland, Oregon, USA., Planck SR; Casey Eye Institute, Oregon Health & Science University Casey Eye Institute, Portland, Oregon, USA.; Devers Eye Institute, Legacy Health System, Portland, Oregon, USA., Korn BS; Oculofacial Plastic and Reconstructive Surgery, University of California San Diego- Shiley Eye Institute and Viterbi Family Department of Ophthalmology, La Jolla, California, USA., Kikkawa D; Oculofacial Plastic and Reconstructive Surgery, University of California San Diego- Shiley Eye Institute and Viterbi Family Department of Ophthalmology, La Jolla, California, USA., Czyz CN; Oculofacial Plastic and Reconstructive Surgery, Ohio Health, Columbus, Ohio, USA., Foster JA; Oculofacial Plastic and Reconstructive Surgery, The Ohio State University, Nationwide Children's Hospital, Ophthalmic Surgeons and Consultants of Ohio, Columbus, Ohio, USA., Kazim M; Edward S Harkness Eye Institute, Columbia University, New York, New York, USA., Harris GJ; Oculofacial Plastic and Reconstructive Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA., Edward DP; Ophthalmology and Visual Sciences, University of Illinois College of Medicine, Chicago, Illinois, USA.; Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia., Al-Hussain H; Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia., Maktabi AMY; Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia., Alabiad C; Oculofacial Plastic and Reconstructive Surgery, University of Miami Health System Bascom Palmer Eye Institute, Miami, Florida, USA., Garcia A; Oculofacial Plastic and Reconstructive Surgery, University of Miami Health System Bascom Palmer Eye Institute, Miami, Florida, USA., Rosenbaum JT; Casey Eye Institute, Oregon Health & Science University Casey Eye Institute, Portland, Oregon, USA rosenbaj@ohsu.edu.; Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA.; Devers Eye Institute, Legacy Health System, Portland, Oregon, USA.
Jazyk:	angličtina
Zdroj:	The British journal of ophthalmology [Br J Ophthalmol] 2022 Jul; Vol. 106 (7), pp. 1012-1017. Date of Electronic Publication: 2021 Feb 26.
DOI:	10.1136/bjophthalmol-2020-318330
Abstrakt:	Background: Orbital inflammatory disease (OID) encompasses a wide range of pathology including thyroid-associated orbitopathy (TAO), granulomatosis with polyangiitis (GPA), sarcoidosis and non-specific orbital inflammation (NSOI), accounting for up to 6% of orbital diseases. Understanding the underlying pathophysiology of OID can improve diagnosis and help target therapy. Aims: To test the hypothesis that shared signalling pathways are activated in different forms of OID. Methods: In this secondary analysis, pathway analysis was performed on the previously reported differentially expressed genes from orbital adipose tissue using patients with OID and healthy controls who were characterised by microarray. For the original publications, tissue specimens were collected from oculoplastic surgeons at 10 international centres representing four countries (USA, Canada, Australia and Saudi Arabia). Diagnoses were independently confirmed by two masked ocular pathologists (DJW, HEG). Gene expression profiling analysis was performed at the Oregon Health & Science University. Eighty-three participants were included: 25 with TAO, 6 with orbital GPA, 7 with orbital sarcoidosis, 25 with NSOI and 20 healthy controls. Results: Among the 83 subjects (mean (SD) age, 52.8 (18.3) years; 70% (n=58) female), those with OID demonstrated perturbation of the downstream gene expressions of the IGF-1R (MAPK/RAS/RAF/MEK/ERK and PI3K/Akt/mTOR pathways), peroxisome proliferator-activated receptor-γ (PPARγ), adipocytokine and AMPK signalling pathways compared with healthy controls. Specifically, GPA samples differed from controls in gene expression within the insulin-like growth factor-1 receptor (IGF-1R, PI3K-Akt (p=0.001), RAS (p=0.005)), PPARγ (p=0.002), adipocytokine (p=0.004) or AMPK (p=<0.001) pathways. TAO, sarcoidosis and NSOI samples were also found to have statistically significant differential gene expression in these pathways. Conclusions: Although OID includes a heterogenous group of pathologies, TAO, GPA, sarcoidosis and NSOI share enrichment of common gene signalling pathways, namely IGF-1R, PPARγ, adipocytokine and AMPK. Pathway analyses of gene expression suggest that other forms of orbital inflammation in addition to TAO may benefit from blockade of IGF-1R signalling pathways. Competing Interests: Competing interests: JTR has in the past consulted for Genentech/Roche and was a coinvestigator on a study funded by Genentech to evaluate the use of rituximab for orbital inflammatory diseases. JTR, RAD, BSK, DOK, and GJH are consultants to Horizon Pharmaceuticals which manufactures teprotumumab. JTR receives research support from Horizon Pharmaceuticals. (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu