Adenosine A2Areceptor promotes collagen type III synthesis via β-catenin activation in human dermal fibroblasts.
Adenosine A2Areceptor stimulation promotes the synthesis of collagen type I and type III (Col1 and Col3), mediators of fibrosis and scarring. The A2Areceptor modulates collagen balance via cAMP/PKA/p38-MAPK/Akt pathways. Wnt signalling is important in fibrosis and the cAMP and Wnt pathways converge. Because the A2Areceptor is Gs-linked and increases cAMP, we determined whether A2Areceptors and Wnt signalling interact.



Total β-catenin, de-phosphorylated β-catenin (canonical activation, de-phospho β-catenin) and phosphorylated β-catenin at Ser552(non-canonical activation, p-Ser552β-catenin) levels were determined in primary human dermal fibroblasts, cytosol and nucleus, by western blot analysis and fluorescence microscopy, before and after stimulation by A2Areceptor-selective agonist CGS21680, with/without A2Areceptor-selective antagonist (SCH56261) pretreatment. β-Catenin was knocked down by transfection with scrambled-siRNA or specific-siRNA, and Col1 and Col3 levels determined by western blots.



CGS21680 stimulation rapidly (15 min) increased cellular β-catenin levels. Both de-phospho β-catenin and p-Ser552β-catenin levels were also increased. CGS21680 stimulated the translocation of total de-phospho and p-Ser552β-catenin to the nucleus. A2Areceptor-stimulation increased Col1 synthesis similarly in β-catenin knockeddown and scrambled cells. However, β-catenin knockdown abolished the increase in Col3 synthesis induced in A2Areceptor-stimulated fibroblasts.



A2Areceptor stimulation promotes Col3 synthesis via the activation of canonical and non-canonical β-catenin, consistent with a role for A2Areceptors in dermal fibrosis and scarring.
Department of Medicine, New York University School of Medicine, New York, NY, USA.
Gibran
G
Shaikh
Department of Medicine, New York University School of Medicine, New York, NY, USA.|Department of Immunology and Rheumatology, LiHuili Hospital, Medical School of Ningbo University, Ningbo, China.
Jin
J
Zhang
Department of Medicine, New York University School of Medicine, New York, NY, USA.
Miguel
M
Perez-Aso
Department of Medicine, New York University School of Medicine, New York, NY, USA.|Bone and Joint Research Unit IIS-Fundación Jiménez Díaz UAM, Madrid, 28040, Spain.
Aranzazu
A
Mediero
Department of Medicine, New York University School of Medicine, New York, NY, USA.
Bruce
B
Cronstein
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D015153:Blotting, Western; D002921:Cicatrix / Q000473:pathology; D024042:Collagen Type I / Q000096:biosynthesis; D024061:Collagen Type III / Q000096:biosynthesis*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D008856:Microscopy, Fluorescence; D010627:Phenethylamines / Q000494:pharmacology; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000008:administration & dosage; D043705:Receptor, Adenosine A2A / Q000187:drug effects / Q000378:metabolism*; D012867:Skin / Q000473:pathology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D024042:Collagen Type I; D024061:Collagen Type III; D010627:Phenethylamines; D034741:RNA, Small Interfering; D043705:Receptor, Adenosine A2A; D051176:beta Catenin; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine