title: Cannabinoids inhibit fibrogenesis in diffuse systemic sclerosis fibroblasts.
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.
authors: Department of Clinical Medicine and Immunological Science, Rheumatology Unit, University of Siena, Siena, Italy. estre79@gmail.com
authors: Estrella
authors: E
authors: Garcia-Gonzalez
authors: Enrico
authors: E
authors: Selvi
authors: Epifania
authors: E
authors: Balistreri
authors: Sauro
authors: S
authors: Lorenzini
authors: Roberta
authors: R
authors: Maggio
authors: Maria-Rita
authors: MR
authors: Natale
authors: Pier-Leopoldo
authors: PL
authors: Capecchi
authors: Pietro-Enea
authors: PE
authors: Lazzerini
authors: Marco
authors: M
authors: Bardelli
authors: Franco
authors: F
authors: Laghi-Pasini
authors: Mauro
authors: M
authors: Galeazzi
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D048588:Benzoxazines / Q000494:pharmacology; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids / Q000819:agonists / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis / Q000235:genetics; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D043882:Receptors, Cannabinoid / Q000378:metabolism; D045743:Scleroderma, Diffuse / Q000378:metabolism / Q000473:pathology*; D012867:Skin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D000093242:Interleukin-6 Inhibitors
chemical_list: D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D024042:Collagen Type I; D055513:Connective Tissue Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009025:Morpholines; D009281:Naphthalenes; D012333:RNA, Messenger; D043882:Receptors, Cannabinoid; D016212:Transforming Growth Factor beta; D000093242:Interleukin-6 Inhibitors; C526317:CCN2 protein, human; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C535150:MAPK1 protein, human