Matrix replacement and repair is required for wound healing but when the process is overly exuberant, as in scar or keloid formation, or when it occurs inappropriately, as in Scleroderma and other fibrosing diseases, it can lead to morbidity and, in the case of Scleroderma, mortality. Although it is clear that growth factors play a central role in fibrosis the role of small molecules in pathologic fibrosis has not been well explored. We have recently demonstrated that the purine nucleoside adenosine, acting through the adenosine A2A receptor, plays a central role in the fibrosis that develops in experimental models of hepatic cirrhosis and scleroderma. We propose here to further determine whether adenosine and adenosine receptors play a role in pathologic fibrosis and to dissect the molecular mechanism by which adenosine A2A receptors on fibroblasts stimulate overproduction of collagen and other matrix constituents. To this end we have proposed to study: I. The role of adenosine receptors in pathologic fibrosis. We will study the development of hypertrophic scarring in a model of dermal scarring and diffuse dermal fibrosis induced by bleomycin treatment in wild type, adenosine A1, A2A, A2B and A3 receptor knockout mice, mice that generate less extracellular adenosine (ecto-5'Nucleotidase and nucleoside triphosphate pyrophosphatase knockout mice) and mice treated with adenosine receptor antagonists;II. Signaling at adenosine A2A receptors for fibrosis In preliminary experiments we have observed that adenosine A2A receptor stimulation diminishes nuclear fli1 levels, a constitutive repressor of CTGF expression, a change which may mediate the pro- fibrotic effects of adenosine and the A2A receptor. We will dissect the signaling pathways from adenosine A2A receptors to suppression of fli1 expression and nuclear localization using a combination of pharmacologic and siRNA-mediated knockdown techniques;III. Cross-talk between adenosine A2A receptors and receptors for """"""""anti-fibrotic"""""""" cytokines We have previously demonstrated that interferon-3, an anti-fibrotic cytokine, diminishes adenosine A2A receptor expression and, more dramatically, function. We will study the mechanism by which interferon-3 downregulates adenosine A2A receptor function with a combination of pharmacologic and molecular (siRNA-mediated knockdown) methods. In future experiments we will examine the role of adenosine receptors in keloid formation and other clinically- relevant forms of pathologic fibrosis (e.g. radiation fibrosis). Because adenosine receptor antagonists are under development for the treatment of a variety of medical conditions it may be possible to quickly bring the information garnered in these studies to the clinic.
The synthesis of new fibrous tissue is a normal process which is critical for wound healing and tissue repair, however excess fibrous tissue formation is a significant medical issue in conditions ranging from Scleroderma (diffuse skin and organ fibrosis that can be life-threatening) to disfiguring scarring or tendon enlargement. Our laboratory has found that adenosine and its receptors play a central role in diffuse fibrosis in animal models of Scleroderma and hypertrophic scarring. We propose studies designed to further confirm the role of adenosine and its receptors in scarring and to discover the mechanism by which adenosine receptors stimulate production of excess fibrous tissue. A better understanding of the role of adenosine and its receptors in fibrosis and the medical problems resulting from fibrosis could facilitate the development of new agents that will prevent the development of enlarged scars or ameliorate the fibrosis that characterizes Scleroderma.
|Haskó, György; Antonioli, Luca; Cronstein, Bruce N (2018) Adenosine metabolism, immunity and joint health. Biochem Pharmacol 151:307-313|
|Yang, Lu; Fanok, Melania H; Mediero-Munoz, Aranzazu et al. (2018) Augmented Th17 Differentiation Leads to Cutaneous and Synovio-Entheseal Inflammation in a Novel Model of Psoriatic Arthritis. Arthritis Rheumatol 70:855-867|
|Mediero, Aránzazu; Wilder, Tuere; Shah, Lopa et al. (2018) Adenosine A2A receptor (A2AR) stimulation modulates expression of semaphorins 4D and 3A, regulators of bone homeostasis. FASEB J 32:3487-3501|
|Ishack, Stephanie; Mediero, Aranzazu; Wilder, Tuere et al. (2017) Bone regeneration in critical bone defects using three-dimensionally printed ?-tricalcium phosphate/hydroxyapatite scaffolds is enhanced by coating scaffolds with either dipyridamole or BMP-2. J Biomed Mater Res B Appl Biomater 105:366-375|
|Feig, Jessica L; Mediero, Aranzazu; Corciulo, Carmen et al. (2017) The antiviral drug tenofovir, an inhibitor of Pannexin-1-mediated ATP release, prevents liver and skin fibrosis by downregulating adenosine levels in the liver and skin. PLoS One 12:e0188135|
|Zhang, Jin; Corciulo, Carmen; Liu, Hailing et al. (2017) Adenosine A2a Receptor Blockade Diminishes Wnt/?-Catenin Signaling in a Murine Model of Bleomycin-Induced Dermal Fibrosis. Am J Pathol 187:1935-1944|
|Bradaschia-Correa, Vivian; Josephson, Anne M; Egol, Alexander J et al. (2017) Ecto-5'-nucleotidase (CD73) regulates bone formation and remodeling during intramembranous bone repair in aging mice. Tissue Cell 49:545-551|
|Cronstein, Bruce N; Sitkovsky, Michail (2017) Adenosine and adenosine receptors in the pathogenesis and treatment of rheumatic diseases. Nat Rev Rheumatol 13:41-51|
|Corciulo, Carmen; Lendhey, Matin; Wilder, Tuere et al. (2017) Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression. Nat Commun 8:15019|
|Mediero, Aránzazu; Wilder, Tuere; Ramkhelawon, Bhama et al. (2016) Netrin-1 and its receptor Unc5b are novel targets for the treatment of inflammatory arthritis. FASEB J 30:3835-3844|
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