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The cannabinoid receptor CB2 exerts antifibrotic effects in experimental dermal fibrosis


Akhmetshina, A; Dees, C; Busch, N; Beer, J; Sarter, K; Zwerina, J; Zimmer, A; Distler, O; Schett, G; Distler, J H W (2009). The cannabinoid receptor CB2 exerts antifibrotic effects in experimental dermal fibrosis. Arthritis and Rheumatism, 60(4):1129-1136.

Abstract

OBJECTIVE: The cannabinoid receptor CB2 is predominantly expressed in non-neuronal tissue and exerts potent immunomodulatory effects. This study was undertaken to evaluate the role of CB2 in the pathogenesis of dermal fibrosis. METHODS: Mice deficient in CB2 (CB2(-/-) mice) and their wild-type littermates (CB2(+/+) mice) were injected with bleomycin to induce experimental fibrosis. Mice were treated with selective agonists and antagonists of CB2. Lesional skin was evaluated for dermal thickness and numbers of infiltrating leukocytes. Bone marrow transplantation experiments were performed. RESULTS: CB2(-/-) mice were more sensitive to bleomycin-induced dermal fibrosis than were CB2(+/+) mice, and showed increased dermal thickness. Leukocyte counts were significantly higher in the lesional skin of CB2(+/+) mice. Increased dermal fibrosis was also observed upon treatment with the CB2 antagonist AM-630. In contrast, the selective CB2 agonist JWH-133 reduced leukocyte infiltration and dermal thickening. The phenotype of CB2(-/-) mice was mimicked by transplantation of CB2(-/-) bone marrow into CB2(+/+) mice, whereas CB2(-/-) mice transplanted with bone marrow from CB2(+/+) mice did not display an increased sensitivity to bleomycin-induced fibrosis, indicating that leukocyte expression of CB2 critically influences experimental fibrosis. CONCLUSION: Our findings indicate that CB2 limits leukocyte infiltration and tissue fibrosis in experimental dermal fibrosis. Since selective CB2 agonists are available and well tolerated, CB2 might be an interesting molecular target for the treatment of early inflammatory stages of systemic sclerosis.

Abstract

OBJECTIVE: The cannabinoid receptor CB2 is predominantly expressed in non-neuronal tissue and exerts potent immunomodulatory effects. This study was undertaken to evaluate the role of CB2 in the pathogenesis of dermal fibrosis. METHODS: Mice deficient in CB2 (CB2(-/-) mice) and their wild-type littermates (CB2(+/+) mice) were injected with bleomycin to induce experimental fibrosis. Mice were treated with selective agonists and antagonists of CB2. Lesional skin was evaluated for dermal thickness and numbers of infiltrating leukocytes. Bone marrow transplantation experiments were performed. RESULTS: CB2(-/-) mice were more sensitive to bleomycin-induced dermal fibrosis than were CB2(+/+) mice, and showed increased dermal thickness. Leukocyte counts were significantly higher in the lesional skin of CB2(+/+) mice. Increased dermal fibrosis was also observed upon treatment with the CB2 antagonist AM-630. In contrast, the selective CB2 agonist JWH-133 reduced leukocyte infiltration and dermal thickening. The phenotype of CB2(-/-) mice was mimicked by transplantation of CB2(-/-) bone marrow into CB2(+/+) mice, whereas CB2(-/-) mice transplanted with bone marrow from CB2(+/+) mice did not display an increased sensitivity to bleomycin-induced fibrosis, indicating that leukocyte expression of CB2 critically influences experimental fibrosis. CONCLUSION: Our findings indicate that CB2 limits leukocyte infiltration and tissue fibrosis in experimental dermal fibrosis. Since selective CB2 agonists are available and well tolerated, CB2 might be an interesting molecular target for the treatment of early inflammatory stages of systemic sclerosis.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Rheumatology Clinic and Institute of Physical Medicine
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Date:April 2009
Deposited On:20 Jan 2010 10:15
Last Modified:05 Apr 2016 13:47
Publisher:Wiley-Blackwell
ISSN:0004-3591
Publisher DOI:https://doi.org/10.1002/art.24395
PubMed ID:19333940

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