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Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis
  1. Estrella Garcia Gonzalez1,
  2. Enrico Selvi1,
  3. Epifania Balistreri1,
  4. Alfiya Akhmetshina2,
  5. Katrin Palumbo2,
  6. Sauro Lorenzini1,
  7. Pietro Enea Lazzerini3,
  8. Cinzia Montilli3,
  9. Pier Leopoldo Capecchi3,
  10. Monica Lucattelli4,
  11. Caterina Baldi1,
  12. Elena Gianchecchi3,
  13. Mauro Galeazzi1,
  14. Franco Laghi Pasini3,
  15. Jörg H W Distler2
  1. 1Department of Clinical Medicine and Immunological Sciences, Rheumatology Unit, Siena, Italy
  2. 2Department of Internal Medicine III, University of Erlangen, Erlangen, Germany
  3. 3Department of Clinical Medicine and Immunological Sciences, Immunology Unit, Siena, Italy
  4. 4Department of Physiopathology, Experimental Medicine and Public Health, Siena, Italy
  1. Correspondence to Estrella Garcia Gonzalez, Rheumatology Unit, Department of Clinical Medicine and Immunological Sciences, Siena 53100, Italy; estre79{at}gmail.com

Abstract

Background Cannabinoids modulate fibrogenesis in scleroderma. Ajulemic acid (AjA) is a non-psychoactive synthetic analogue of tetrahydrocannabinol that can bind the peroxisome proliferator-activated receptor-γ (PPAR-γ). Recent evidence suggests a key role for PPAR-γ in fibrogenesis.

Objective To determine whether AjA can modulate fibrogenesis in murine models of scleroderma.

Material and methods Bleomycin-induced experimental fibrosis was used to assess the antifibrotic effects of AjA in vivo. In addition, the efficacy of AjA in pre-established fibrosis was analysed in a modified model of bleomycin-induced dermal fibrosis and in mice overexpressing a constitutively active transforming growth factor β (TGFβ) receptor I. Skin fibrosis was evaluated by quantification of skin thickness and hydroxyproline content. As a marker of fibroblast activation, α-smooth muscle actin was examined. To study the direct effect of AjA in collagen neosynthesis, skin fibroblasts from patients with scleroderma were treated with increasing concentrations of AjA. Protein expression of PPAR-γ, and its endogenous ligand 15d-PGJ2, and TGFβ were assessed before and after AjA treatment.

Results AjA significantly prevented experimental bleomycin-induced dermal fibrosis and modestly reduced its progression when started 3 weeks into the disease. AjA strongly reduced collagen neosynthesis by scleroderma fibroblasts in vitro, an action which was reversed completely by co-treatment with a selective PPAR-γ antagonist.

Conclusions AjA prevents progression of fibrosis in vivo and inhibits fibrogenesis in vitro by stimulating PPAR-γ signalling. Since therapeutic doses of AjA are well tolerated in humans, it is suggested that AjA as an interesting molecule targeting fibrosis in patients with scleroderma.

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Footnotes

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it was published Online First.

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