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We have previously found that adenosine, acting via receptors (A2AR) promotes wound healing and inhibits inflammatory osteolysis and hypothesized that A2AR might be a novel target to promote bone regeneration. Therefore, we determined whether direct A2AR stimulation or increasing endogenous adenosine concentrations\n                    <jats:italic>via<\/jats:italic>\n                    purine transport blockade with dipyridamole regulates bone formation. We determined whether coverage of a 3 mm trephine defect in a mouse skull with a collagen scaffold soaked in saline, bone morphogenetic protein\u20102 (BMP\u20102; 200 ng), 1 \u03bcM CGS21680 (A2AR agonist, EC\n                    <jats:sub>50<\/jats:sub>\n                    = 160 nM), or 1 \u03bcM dipyridamole (EC\n                    <jats:sub>50<\/jats:sub>\n                    = 32 nM) promoted bone regeneration. Microcomputed tomography examination demonstrated that CGS21680 and dipyridamole markedly enhanced bone regeneration as well as BMP\u20102 8 wk after surgery (60 \u00b1 2%, 79 \u00b1 2%, and 75 \u00b1 1% bone regeneration, respectively,\n                    <jats:italic>vs.<\/jats:italic>\n                    32 \u00b1 2% in control,\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.001). Blockade by a selective A2AR antagonist (ZM241385, 1 \u03bcM) or deletion of A2AR abrogated the effect of CGS21680 and dipyridamole on bone regeneration. Both CGS21680 and dipyridamole treatment increased alkaline phosphatase\u2010positive osteoblasts and diminished tartrate resistance acid phosphatase\u2010positive osteoclasts in the defects.\n                    <jats:italic>In vivo<\/jats:italic>\n                    imaging with a fluorescent dye for new bone formation revealed a strong fluorescent signal in treated animals that was equivalent to BMP\u20102. In conclusion, stimulation of A2AR by specific agonists or by increasing endogenous adenosine levels stimulates new bone formation as well as BMP\u20102 and represents a novel approach to stimulating bone regeneration.\u2014Mediero, A., Wilder, T., Perez\u2010Aso, M., Cronstein, B. N. Direct or indirect stimulation of adenosine A\n                    <jats:sub>2A<\/jats:sub>\n                    receptors enhances bone regeneration as well as bone morphogenetic protein\u20102.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    29, 1577\u20101590 (2015).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.14-265066","type":"journal-article","created":{"date-parts":[[2015,1,9]],"date-time":"2015-01-09T02:53:51Z","timestamp":1420772031000},"page":"1577-1590","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":98,"title":["Direct or indirect stimulation of adenosine A\n                    <sub>2A<\/sub>\n                    receptors enhances bone regeneration as well as bone morphogenetic protein\u20102"],"prefix":"10.1096","volume":"29","author":[{"given":"Ar\u00e1nzazu","family":"Mediero","sequence":"first","affiliation":[{"name":"Divisions of Translational Medicine and Rheumatology Department of Medicine New York University Langone Medical Center New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuere","family":"Wilder","sequence":"additional","affiliation":[{"name":"Divisions of Translational Medicine and Rheumatology Department of Medicine New York University Langone Medical Center New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Perez\u2010Aso","sequence":"additional","affiliation":[{"name":"Divisions of Translational Medicine and Rheumatology Department of Medicine New York University Langone Medical Center New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce N.","family":"Cronstein","sequence":"additional","affiliation":[{"name":"Divisions of Translational Medicine and Rheumatology Department of Medicine New York University Langone Medical Center New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,1,8]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2008.07.004"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.injury.2007.02.006"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOT.0b013e3181ed1361"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/00003086-199603000-00006"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007632-200212010-00005"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(98)00056-8"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0736-0266(02)00205-X"},{"key":"e_1_2_7_9_1","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1080\/08941930290085822","article-title":"Healing course of primate ulna segmental defects treated with osteogenic protein\u20101","volume":"5","author":"Cook S. 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