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FGF9-induced proliferative response to eosinophilic inflammation in oesophagitis
  1. D J Mulder1,2,
  2. I Pacheco2,
  3. D J Hurlbut3,
  4. N Mak2,
  5. G T Furuta4,
  6. R J MacLeod2,5,
  7. C J Justinich2,6,6
  1. 1
    Department of Anatomy and Cell Biology, Queen’s University, Kingston, Ontario, Canada
  2. 2
    Gastrointestinal Diseases Research Unit, Kingston General Hospital, Kingston, Ontario, Canada
  3. 3
    Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Ontario, Canada
  4. 4
    Section of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital Denver, University of Colorado Denver, Aurora, Colorado, USA
  5. 5
    Departments of Physiology and Medicine, Queen’s University, Kingston, Ontario, Canada
  6. 6
    Pediatric Gastroenterology, Departments of Pediatrics, Anatomy and Cell Biology, Physiology and Medicine, Queen’s University, Kingston, Ontario, Canada
  1. Dr C Justinich, Queen’s University, Kingston, ON, Canada K7L 3N6; justinic{at}kgh.kari.net

Abstract

Background: Oesophagitis is characterised by basal cell hyperplasia and activated eosinophils, which release mediators including major basic protein (MBP). MBP and its mimetic polyarginine activate the calcium sensing receptor (CaSR) on oesophageal epithelium. Fibroblast growth factor 9 (FGF9) is implicated in epithelial homeostasis and proliferative response to injury, but has not been characterised in the oesophagus.

Objective: To characterise FGF9 in oesophageal epithelium and oesophagitis, as the result of MBP activation of the CaSR.

Methods: Human oesophageal epithelial cells (HET-1A) were used to compare affects of calcium, polyarginine and MBP-peptide on FGF9. HET-1A were transfected with interfering RNA (siRNACaSR). FGF9, FGF receptors 2 and 3, bone morphogenetic protein (BMP)-2, BMP-4 and noggin mRNA expression were detected by reverse transcriptase polymerase chain reaction. FGF9 was measured from HET-1A and from normal, gastro-oesophageal reflux and eosinophilic oesophagitis (EoE) patient biopsies using ELISA and immunohistochemistry. HET-1A proliferation was studied using bromodeoxyuridine and MTT.

Results: FGF9 was secreted by HET-1A cells treated with polyarginine and MBP-peptide, but not calcium. This effect was abrogated by siRNACaSR. FGF9 receptor mRNA was present. HET-1A cells proliferated following rhFGF9, but not MBP-peptide treatment, and rhFGF9 altered transcription of downstream proliferation-related genes (noggin, BMP-2 and BMP-4). FGF9 was increased in biopsies from patients with eosinophilic oesophagitis, which correlated with basal hyperplasia.

Conclusion: Eosinophil-released MBP acts on the CaSR to increase FGF9 in oesophageal epithelial cells, leading to proliferation. Increased FGF9 is found in biopsies of EoE patients and may play a role in the pathogenesis of oesophagitis.

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Footnotes

  • A supplementary file giving the full gene array is published online only at http://gut.bmj.com/content/vol58/issue2

  • Funding: This work was supported by grants from the Physicians’ Services Incorporated Foundation (R 05–21, CJJ) and from the Canadian Institutes for Health Research and the Canadian Crohn’s and Colitis Foundation (RJM). We acknowledge support from Kingston General Hospital and the Queen’s University Gastrointestinal Diseases Research Unit.

  • Competing interests: None.

  • Ethics approval: This study was performed in accordance with the Queen’s University Research Ethics Board, and was approved on 1 December 2004.

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