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Loss of imprinting of IGF2 characterises high IGF2 mRNA-expressing type of fibroblast-like synoviocytes in rheumatoid arthritis
  1. Alejandro Martin-Trujillo1,2,
  2. Johanna G I van Rietschoten3,
  3. Trieneke C G Timmer1,3,
  4. Francisco Milena Rodríguez1,
  5. Tom W J Huizinga4,
  6. Paul P Tak5,
  7. Sara Marsal2,
  8. Saleh M Ibrahim6,
  9. Ben A C Dijkmans7,
  10. Tineke C T M van der Pouw Kraan3,
  11. Cornelis L Verweij1,7
  1. 1Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
  2. 2Grup de Recerca de Reumatologia, Institut de Recerca de l'Hospital Universitari Vall d'Hebrón, Barcelona, Spain
  3. 3Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
  4. 4Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  5. 5Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  6. 6Section of Immunogenetics, University of Rostock, Rostock, Germany
  7. 7Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands
  1. Correspondence to Dr Cornelis L Verweij, VU University Medical Center, Department of Pathology and Rheumatology, CCA 2.60, PO Box 7057, 1007 MB Amsterdam, The Netherlands; c.verweij{at}


Objective Increased expression of insulin-like growth factor 2 (IGF2) by fibroblast-like synoviocytes (FLS) was associated with low inflammatory synovium of patients with rheumatoid arthritis (RA). The aim of this study was to analyse whether the differential expression of IGF2, whose expression is normally restricted to one allele, is due to activation of the normally suppressed allele.

Methods IGF2 gene expression of RA FLS was quantified by quantitative real-time PCR. FLS heterozygous for a 3′-untranslated region IGF2 polymorphism were selected to measure the relative contribution of the allelic transcripts by allele-specific transcript quantification assay. Proliferation was determined by [3H]thymidine incorporation.

Results IGF2 was shown to contribute to RA FLS proliferation. FLS could be classified in IGF2 high and IGF2 low-expressing cell lines. Allelic IGF2 transcript quantification analysis revealed that in part of the RA FLS the normally suppressed allele was activated, resulting in biallelic expression of the IGF2 gene. Biallelic expression was associated with increased levels of IGF2 mRNA production.

Conclusion The findings indicate that the imprinting status of IGF2 might underlie the increased expression of IGF2, which may contribute to autonomous growth of RA FLS of low inflammatory synovial tissues.

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  • AM-T and JGIR contributed equally.

  • Funding This work has been funded by the EU FP6 Marie Curie Training Network EURORA, the EU FP6 integrated program AUTOCURE, the Innovation Oriented research Program (IOP) on Genomics and Centre for Medical Systems Biology (CMSB, a centre of excellence approved by The Netherlands Genomics Initiative/Netherlands Organization for Scientific Research). This publication reflects only the authors' views. The European Community is not liable for any use that may be made of the information herein.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval The Medical Ethics Committee approved this study.

  • Provenance and peer review Not commissioned; externally peer reviewed.