Transcriptome-level microarray expression profiling implicates IGF-1 and Wnt signalling dysregulation in the pathogenesis of thyroid-associated orbitopathy
- Daniel G Ezra1,2,3,4,
- Jonathan Krell4,
- Geoffrey E Rose1,3,
- Maryse Bailly1,2,
- Justin Stebbing4,
- Leandro Castellano4
- 1NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital, London, UK
- 2Department of Cell Biology, UCL Institute of Ophthalmology, London, UK
- 3The Orbital Clinic, Moorfields Eye Hospital NHS Trust, London, UK
- 4Department of Surgery and Cancer, Imperial College, Hammersmith Hospital, London, UK
- Correspondence to Daniel G Ezra, NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital and UCL Institute of Ophthalmology, Moorfields Eye Hospital NHS Trust, City Road, London EC1V 2PD, UK;
Contributors Conception and design: DE,JS,GR, MB. Data analysis/interpretation: DE,JS, LC,JK, MB. Drafting and revision: DE,JK,GR,JS,LC, MB. Final approval: DE,JK,GR,JS,LC,MB.
- Accepted 15 February 2012
- Published Online First 3 May 2012
Aims The pathogenesis of thyroid-associated orbitopathy (TAO) remains unclear. The aim of this study is to elucidate the gene expression profile of orbital fat from patients with active, but untreated, TAO.
Methods A case–control gene expression study was conducted using test samples of orbital fat from TAO patients and control orbital fat specimens; apart from drugs to control thyrotoxicosis, the TAO patients had received no treatment for orbital disease. cDNA expression analysis was performed using the Affymetrix GeneChip Human Genome U133 Plus 2.0 platform and validated using quantitative PCR.
Results The highest-ranked differentially expressed genes were dominated by IGF-1 signalling genes. These include IGF-1, IGF-1 receptor binding/signalling genes, such as SOCS3 and IRS2, and downstream signalling and transcriptional regulators, such as SGK (PDK/Akt signalling) and c-JUN. Our microarray data also demonstrate dysregulation of wingless-type MMTV (Wnt) signalling gene expression, including Wnt5a, sFRPs and DKK.
Conclusion Altered Wnt signalling confirms previous array findings. Further investigation of the role of Wnt signalling in TAO pathogenesis is warranted. These data also provide the first evidence of dysregulation of IGF-1 pathway genes in TAO tissue, further strengthening the evidence for the role of IGF-1 signalling in the pathogenesis and potential treatment of TAO.
Funding This study was funded bya Society for Endocrinology early career award (DGE) and Academy of Medical Sciences and Wellcome clinical lecturer starter grant (DGE). The authors acknowledge a proportion of their financial support from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health.
Competing interests None.
Patient consent Obtained.
Ethics approval Moorfields Eye Hospital research governance committee.
Provenance and peer review Not commissioned; externally peer reviewed.