Our preliminary findings suggest that cannabinoids are provided with an anti-fibrotic activity, thereby possibly representing a new class of agents targeting fibrosis diseases.
Systemic sclerosis (SSc) is a connective tissue disease characterised by exaggerated collagen deposition in the skin and visceral organs. Adenosine A2A receptor stimulation (A2Ar) promotes dermal fibrosis, while the cannabinoid system modulates fibrogenesis in vitro and in animal models of SSc. Moreover, evidence in central nervous system suggests that A2A and cannabinoid (CB1) receptors may physically and functionally interact. On this basis, we investigated A2Ar expression and function in modulating collagen biosynthesis from SSc dermal fibroblasts and analysed the cross-talk with cannabinoid receptors. In sclerodermic cells, A2Ar expression (RT-PCR, Western blotting) was evaluated together with the effects of A2A agonists and/or antagonists on collagen biosynthesis (EIA, Western blotting). Putative physical and functional interactions between the A2A and cannabinoid receptors were respectively assessed by co-immuno-precipitation and co-incubating the cells with the unselective cannabinoid agonist WIN55,212-2, and the selective A2A antagonist ZM-241385. In SSc fibroblasts, (1) the A2Ar is overexpressed and its occupancy with the selective agonist CGS-21680 increases collagen production, myofibroblast trans-differentiation, and ERK-1/2 phosphorylation; (2) the A2Ar forms an heteromer with the cannabinoid CB1 receptor; and (3) unselective cannabinoid receptor stimulation with a per se ineffective dose of WIN55,212-2, results in a marked anti-fibrotic effect after A2Ar blockage. In conclusion, A2Ar stimulation induces a pro-fibrotic phenotype in SSc dermal fibroblasts, either directly, and indirectly, by activating the CB1 cannabinoid receptor. These findings increase our knowledge of the pathophysiology of sclerodermic fibrosis also further suggesting a new therapeutic approach to the disease.
Objectives There is increasing evidence that the endocannabinoid system may be involved in pathological fi brosis, and that its modulation might limit fi brotic responses. The aim of this study was to examine the capacity of a synthetic cannabinoid receptor agonist to modify skin fi brosis in the bleomycin mouse model of scleroderma. Methods Skin fi brosis was induced by local injections of bleomycin in two groups of DBA/2J mice. One group was cotreated with the synthetic cannabinoid WIN55,212-2 at 1 mg/kg/day. Skin fi brosis was evaluated by histology and skin thickness and hydroxyproline content were quantifi ed. Markers of fi broblast activation, including α smooth muscle actin and the profi brotic cytokines transforming growth factor (TGF)β, connective tissue growth factor (CTGF) and platelet-derived growth factor (PDGF)-BB, were examined. Levels of PSMAD2/3, which are crucial in extracellular matrix overproduction, were analysed. Results Bleomycin treatment induced typical skin fi brosis. Upon WIN55,212-2 treatment dermal fi brosis was completely prevented. Subcutaneous infl ammatory cell infi ltration, dermal thickness and collagen content resulted similar to those of the control group. The synthetic cannabinoid prevented fi broblasts activation induced by bleomycin, paralleled by a strong inhibition of TGFβ, CTGF and PDGF-BB expression. Phosphorylation of SMAD2/3 was signifi cantly downregulated after WIN55,212-2 exposure. Conclusions Taken together, the results indicate that the synthetic cannabinoid WIN55,212-2 is capable of preventing skin fi brosis in a mouse model of scleroderma.
These findings indicate that more informative than comparing changes in absolute levels of EPCs, the examination of their relationship with clinical characteristics of RA patients can reveal significant associations, which may provide important clinical insights.
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