Cannabinoids inhibit fibrogenesis in diffuse systemic sclerosis fibroblasts.
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.
Garcia-Gonzalez
Estrella
E
Department of Clinical Medicine and Immunological Science, Rheumatology Unit, University of Siena, Siena, Italy. estre79@gmail.com
Selvi
Enrico
E
Balistreri
Epifania
E
Lorenzini
Sauro
S
Maggio
Roberta
R
Natale
Maria-Rita
MR
Capecchi
Pier-Leopoldo
PL
Lazzerini
Pietro-Enea
PE
Bardelli
Marco
M
Laghi-Pasini
Franco
F
Galeazzi
Mauro
M
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
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