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Adenosine A2A receptor promotes collagen type III synthesis via ?-catenin activation in human dermal fibroblasts.

ABSTRACT: BACKGROUND AND PURPOSE:Adenosine A2A receptor stimulation promotes the synthesis of collagen type I and type III (Col1 and Col3), mediators of fibrosis and scarring. The A2A receptor 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 A2A receptor is Gs-linked and increases cAMP, we determined whether A2A receptors and Wnt signalling interact. EXPERIMENTAL APPROACH:Total ?-catenin, de-phosphorylated ?-catenin (canonical activation, de-phospho ?-catenin) and phosphorylated ?-catenin at Ser552 (non-canonical activation, p-Ser552 ?-catenin) levels were determined in primary human dermal fibroblasts, cytosol and nucleus, by western blot analysis and fluorescence microscopy, before and after stimulation by A2A receptor-selective agonist CGS21680, with/without A2A receptor-selective antagonist (SCH56261) pretreatment. ?-Catenin was knocked down by transfection with scrambled-siRNA or specific-siRNA, and Col1 and Col3 levels determined by western blots. KEY RESULTS:CGS21680 stimulation rapidly (15 min) increased cellular ?-catenin levels. Both de-phospho ?-catenin and p-Ser552 ?-catenin levels were also increased. CGS21680 stimulated the translocation of total de-phospho and p-Ser552 ?-catenin to the nucleus. A2A receptor-stimulation increased Col1 synthesis similarly in ?-catenin knockeddown and scrambled cells. However, ?-catenin knockdown abolished the increase in Col3 synthesis induced in A2A receptor-stimulated fibroblasts. CONCLUSIONS AND IMPLICATIONS:A2A receptor stimulation promotes Col3 synthesis via the activation of canonical and non-canonical ?-catenin, consistent with a role for A2A receptors in dermal fibrosis and scarring.

SUBMITTER: Shaikh G

PROVIDER: S-EPMC5738670 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Adenosine A2A receptor promotes collagen type III synthesis via β-catenin activation in human dermal fibroblasts.

Shaikh Gibran G Zhang Jin J Perez-Aso Miguel M Mediero Aranzazu A Cronstein Bruce B

British journal of pharmacology 20161004 23

<h4>Background and purpose</h4>Adenosine A2A receptor stimulation promotes the synthesis of collagen type I and type III (Col1 and Col3), mediators of fibrosis and scarring. The A2A receptor 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 A2A receptor is Gs-linked and increases cAMP, we determined whether A2A receptors and Wnt signalling interact. ...[more]

PMID: 27595240

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Project description:Autophagy, a homeostatic pathway upregulated during cellular stress, is decreased in osteoarthritic chondrocytes and this reduction in autophagy is thought to contribute to the development and progression of osteoarthritis (OA). The adenosine A2A receptor (A2AR) is a potent anti-inflammatory receptor and deficiency of this receptor leads to the development of OA in mice. Moreover, treatment using liposomally conjugated adenosine or a specific A2AR agonist improved joint scores significantly in both rats with post-traumatic OA (PTOA) and mice subjected to a high fat diet obesity induced OA. Importantly, A2AR ligation is beneficial for mitochondrial health and metabolism in vitro in primary and the TC28a2 human cell line. An additional set of metabolic, stress-responsive, and homeostatic mediators include the Forkhead box O transcription factors (FoxOs). Data has shown that mouse FoxO knockouts develop early OA with reduced cartilage autophagy, indicating that FoxO-induced homeostasis is important for articular cartilage. Given the apparent similarities between A2AR and FoxO signaling, we tested the hypothesis that A2AR stimulation improves cartilage function through activation of the FoxO proteins leading to increased autophagy in chondrocytes. We analyzed the signaling pathway in the human TC28a2 cell line and corroborated these findings in vivo in a metabolically relevant obesity-induced OA mouse model. We found that A2AR stimulation increases activation and nuclear localization of FoxO1 and FoxO3, promotes an increase in autophagic flux, improves metabolic function in chondrocytes, and reduces markers of apoptosis in vitro and reduced apoptosis by TUNEL assay in vivo. A2AR ligation additionally enhances in vivo activation of FoxO1 and FoxO3 with evidence of enhanced autophagic flux upon injection of the liposome-associated A2AR agonist in a mouse obesity-induced OA model. These findings offer further evidence that A2AR may be an excellent target for promoting chondrocyte and cartilage homeostasis.

Dataset Information

Adenosine A2A receptor promotes collagen type III synthesis via ?-catenin activation in human dermal fibroblasts.

Publications

Adenosine A<sub>2A</sub> receptor promotes collagen type III synthesis via β-catenin activation in human dermal fibroblasts.

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