title: Extracellular generation of adenosine by the ectonucleotidases CD39 and CD73 promotes dermal fibrosis.
abstract: Adenosine has an important role in inflammation and tissue remodeling and promotes dermal fibrosis by adenosine receptor (A2AR) activation. Adenosine may be formed intracellularly from adenine nucleotides or extracellularly through sequential phosphohydrolysis of released ATP by nucleoside triphosphate diphosphohydrolase (CD39) and ecto-5'-nucleotidase (CD73). Because the role of these ecto-enzymes in fibrosis appears to be tissue specific, we determined whether these ectonucleotidases were directly involved in diffuse dermal fibrosis. Wild-type and mice globally deficient in CD39 knockout (CD39KO), CD73 (CD73KO), or both (CD39/CD73DKO) were challenged with bleomycin. Extracellular adenosine levels and dermal fibrosis were quantitated. Adenosine release from skin cultured ex vivo was increased in wild-type mice after bleomycin treatment but remained low in skin from CD39KO, CD73KO, or CD39/CD73DKO bleomycin-treated mice. Deletion of CD39 and/or CD73 decreased the collagen content, and prevented skin thickening and tensile strength increase after bleomycin challenge. Decreased dermal fibrotic features were associated with reduced expression of the profibrotic mediators, transforming growth factor-β1 and connective tissue growth factor, and diminished myofibroblast population in CD39- and/or CD73-deficient mice. Our work supports the hypothesis that extracellular adenosine, generated in tandem by ecto-enzymes CD39 and CD73, promotes dermal fibrogenesis. We suggest that biochemical or biological inhibitors of CD39 and/or CD73 may hold promise in the treatment of dermal fibrosis in diseases such as scleroderma.
authors.affiliation: Departments of Medicine and Dermatology, New York University School of Medicine, New York, New York.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fernández
authors.affiliation: Departments of Medicine and Dermatology, New York University School of Medicine, New York, New York.
authors.forename: Miguel
authors.initials: M
authors.lastname: Perez-Aso
authors.affiliation: Division of Gastroenterology, Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Gideon
authors.initials: G
authors.lastname: Smith
authors.affiliation: Departments of Medicine and Dermatology, New York University School of Medicine, New York, New York.
authors.forename: Tuere
authors.initials: T
authors.lastname: Wilder
authors.affiliation: Departments of Medicine and Dermatology, New York University School of Medicine, New York, New York.
authors.forename: Sean
authors.initials: S
authors.lastname: Trzaska
authors.affiliation: Departments of Medicine and Dermatology, New York University School of Medicine, New York, New York.
authors.forename: Luis
authors.initials: L
authors.lastname: Chiriboga
authors.affiliation: Departments of Medicine and Dermatology, New York University School of Medicine, New York, New York.
authors.forename: Andrew
authors.initials: A
authors.lastname: Franks
authors.affiliation: Division of Gastroenterology, Department of Medicine, Harvard Medical School, Boston, Massachusetts.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.affiliation: Departments of Medicine and Dermatology, New York University School of Medicine, New York, New York.
authors.forename: Bruce N
authors.initials: BN
authors.lastname: Cronstein
authors.affiliation: Departments of Medicine and Dermatology, New York University School of Medicine, New York, New York. Electronic address: chane01@nyu.edu.
authors.forename: Edwin S L
authors.initials: ESL
authors.lastname: Chan
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism; D000241:Adenosine / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001081:Apyrase / Q000235:genetics / Q000378:metabolism; D001761:Bleomycin / Q000009:adverse effects / Q000494:pharmacology; D020405:Dermis / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D015703:Antigens, CD; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D015720:5'-Nucleotidase; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine