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Changes in biomarkers after therapeutic intervention in temporal arteries cultured in Matrigel: a new model for preclinical studies in giant-cell arteritis
  1. Marc Corbera-Bellalta1,
  2. Ana García-Martínez1,2,
  3. Ester Lozano1,
  4. Ester Planas-Rigol1,
  5. Itziar Tavera-Bahillo1,
  6. Marco A Alba1,
  7. Sergio Prieto-González1,
  8. Montserrat Butjosa1,
  9. Georgina Espígol-Frigolé1,
  10. José Hernández-Rodríguez1,
  11. Pedro L Fernández3,
  12. Pascale Roux-Lombard4,
  13. Jean-Michel Dayer5,
  14. Mahboob U Rahman6,7,
  15. Maria C Cid1
  1. 1Vasculitis Research Unit, Department of Systemic Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
  2. 2Department of Emergency Medicine, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
  3. 3Department of Pathology, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
  4. 4Immunology and Allergy Division, University Hospital of Geneva, Geneva, Switzerland
  5. 5Faculty of Medicine, University of Geneva, Geneva, Switzerland
  6. 6Department of Medicine, Rheumatology section, University of Pennsylvania Medical School, Philadelphia, Pennsylvania, USA
  7. 7Department of Medical Affairs, Emerging Markets Business unit, Pfizer Inc., Collegeville, Pennsylvania, USA
  1. Correspondence to Dr Maria C Cid, Vasculitis Research Unit, Department of Systemic Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Villarroel 170, 08036-Barcelona, Catalonia Spain; mccid{at}clinic.ub.es

Abstract

Background Search for therapeutic targets in giant-cell arteritis (GCA) is hampered by the scarcity of functional systems. We developed a new model consisting of temporal artery culture in tri-dimensional matrix and assessed changes in biomarkers induced by glucocorticoid treatment.

Methods Temporal artery sections from 28 patients with GCA and 22 controls were cultured in Matrigel for 5 days in the presence or the absence of dexamethasone. Tissue mRNA concentrations of pro-inflammatory mediators and vascular remodelling molecules was assessed by real-time RT-PCR. Soluble molecules were measured in the supernatant fluid by immunoassay.

Results Histopathological features were exquisitely preserved in cultured arteries. mRNA concentrations of pro-inflammatory cytokines (particularly IL-1β and IFNγ), chemokines (CCL3/MIP-1α, CCL4/MIP-1β, CCL5/RANTES) and MMP-9 as well as IL-1β and MMP-9 protein concentrations in the supernatants were significantly higher in cultured arteries from patients compared with control arteries. The culture system itself upregulated expression of cytokines and vascular remodelling factors in control arteries. This minimised differences between patients and controls but underlines the relevance of changes observed. Dexamethasone downregulated pro-inflammatory mediator (IL-1β, IL-6, TNFα, IFNγ, MMP-9, TIMP-1, CCL3 and CXCL8) mRNAs but did not modify expression of vascular remodelling factors (platelet derived growth factor, MMP-2 and collagens I and III).

Conclusions Differences in gene expression in temporal arteries from patients and controls are preserved during temporal artery culture in tri-dimensional matrix. Changes in biomarkers elicited by glucocorticoid treatment satisfactorily parallel results obtained in vivo. This may be a suitable model to explore pathogenetic pathways and to perform preclinical studies with new therapeutic agents.

  • Systemic vasculitis
  • Giant Cell Arteritis
  • Chemokines
  • Cytokines
  • Corticosteroids

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