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Rheumatology Advance Access published online on July 9, 2009
Rheumatology, doi:10.1093/rheumatology/kep189
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© The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cannabinoids inhibit fibrogenesis in diffuse systemic sclerosis fibroblasts

Estrella Garcia-Gonzalez1, Enrico Selvi1, Epifania Balistreri1, Sauro Lorenzini1, Roberta Maggio1, Maria-Rita Natale2, Pier-Leopoldo Capecchi2, Pietro-Enea Lazzerini2, Marco Bardelli1, Franco Laghi-Pasini2 and Mauro Galeazzi1

1Department of Clinical Medicine and Immunological Science, Rheumatology Unit and 2Department of Clinical Medicine and Immunological Science, Immunology Unit, University of Siena, Siena, Italy.

Correspondence to: Estrella Garcia-Gonzalez, Policlinico le Scotte, V.le Bracci 1 53100, Siena, Italy. E-mail: estre79{at}gmail.com


  Abstract

Objective. It has been demonstrated that the endocannabinoid system is up-regulated in pathologic fibrosis and that modulation of the cannabinoid receptors might limit the progression of uncontrolled fibrogenesis. The aim of this study was to investigate whether the synthetic cannabinoid receptor agonist WIN55,212-2 could modulate fibrogenesis in an in vitro model of dcSSc.

Methods. The expression of cannabinoid receptors CB1 and CB2 was assessed in dcSSc fibroblasts and healthy control fibroblasts. To investigate the effect of WIN55,212-2 on dcSSc fibrogenesis, we studied type I collagen, profibrotic cytokines, fibroblast transdifferentiation into myofibroblasts, apoptotic processes and activation of the extracellular signal-related kinase 1/2 pathway prior to and after the treatment with the synthetic cannabinoid at increasing concentrations.

Results. Both CB1 and CB2 receptors were over-expressed in dcSSc fibroblasts compared with healthy controls. WIN55,212-2 caused a reduction in extracellular matrix deposition and counteracted several behavioural abnormalities of scleroderma fibroblasts including transdifferentiation into myofibroblasts and resistance to apoptosis. The anti-fibrogenic effect of WIN55,212-2 was not reverted by selective cannabinoid antagonists.

Conclusions. Our preliminary findings suggest that cannabinoids are provided with an anti-fibrotic activity, thereby possibly representing a new class of agents targeting fibrosis diseases.

KEY WORDS: Systemic sclerosis, Cannabinoids, Fibrogenesis, Fibroblasts

Submitted 6 February 2009; revised version accepted 4 June 2009.
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