{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T19:15:34Z","timestamp":1791832534740,"version":"4.3.4"},"reference-count":50,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2018,2,2]],"date-time":"2018-02-02T00:00:00Z","timestamp":1517529600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR68593"],"award-info":[{"award-number":["AR68593"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR56672"],"award-info":[{"award-number":["AR56672"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012799","name":"Clinical and Translational Science Institute, New York University","doi-asserted-by":"publisher","award":["U54TR001364"],"award-info":[{"award-number":["U54TR001364"]}],"id":[{"id":"10.13039\/100012799","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["9NIH\/ NCI 5 P30CA16087\u2010310"],"award-info":[{"award-number":["9NIH\/ NCI 5 P30CA16087\u2010310"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CP15\/00053"],"award-info":[{"award-number":["CP15\/00053"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI16\/00991"],"award-info":[{"award-number":["PI16\/00991"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2018,7]]},"abstract":"<jats:p>\n                    The axonal guidance proteins semaphorin (Sema)4D and Sema3A play important roles in communication between osteoclasts and osteoblasts. As stimulation of adenosine A\n                    <jats:sub>2A<\/jats:sub>\n                    receptors (A2AR) regulates both osteoclast and osteoblast function, we asked whether A2AR regulates both osteoclast and osteoblast expression of Semas. In\n                    <jats:italic>vivo<\/jats:italic>\n                    bone formation and Sema3A\/PlexinA1\/Neuropilin\u20101, Sema4D\/PlexinB1 protein expression were studied in a murine model of wear particle\u2010induced osteolysis. Osteoclast\/osteoblast differentiation were studied in\n                    <jats:italic>vitro<\/jats:italic>\n                    as the number of tartrate\u2010resistant acid phosphatase\n                    <jats:sup>+<\/jats:sup>\n                    \/Alizarin Red\n                    <jats:sup>+<\/jats:sup>\n                    cells after challenge with CGS21680 (A2AR agonist, 1 \u00b5M) or ZM241385 (A2AR antagonist, 1 \u00b5M), with or without Sema4D or Sema3A (10 ng\/ml). Sema3A\/PlexinA1\/ Neuropilin\u20101, Sema4D\/PlexinB1, and receptor activator of NF\u2010\u03baB ligand\/osteoprotegerin (RANKL\/OPG) expression was studied by RT\u2010PCR and Western blot. \u03b2\u2010Catenin activation and cytoskeleton changes were studied by fluorescence microscopy and Western blot. In mice with wear particles implanted over the calvaria, CGS21680 treatment increased bone formation\n                    <jats:italic>in vivo<\/jats:italic>\n                    , reduced Sema4D, and increased Sema3A expression compared with mice with wear particle\u2010induced osteolysis treated with vehicle alone. During osteoclast differentiation, CGS21680 abrogated RANKL\u2010induced Sema4D mRNA expression (1.3 \u00b10.3\u2010\n                    <jats:italic>vs.<\/jats:italic>\n                    2.5 \u00b1 0.1\u2010fold change,\n                    <jats:italic>P &lt;<\/jats:italic>\n                    0.001,\n                    <jats:italic>n<\/jats:italic>\n                    = 4). PlexinA1, but not Neuropilin\u20101, mRNA was enhanced by CGS21680 treatment. CGS21680 enhanced Sema3A mRNA expression during osteoblast differentiation (8.7 \u00b1 0.2\u2010fold increase,\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.001,\n                    <jats:italic>n<\/jats:italic>\n                    = 4); PlexinB1 mRNA was increased 2\u2010fold during osteoblast differentiation and was not altered by CGS21680. Similar changes were observed at the protein level. CGS21680 decreased RANKL, increased OPG, and increased total\/nuclear \u03b2\u2010catenin expression in osteoblasts. Sema4D increased Ras homolog gene family, member A phosphorylation and focal adhesion kinase activation in osteoclast precursors, and CGS21680 abrogated these effects. In summary, A2AR activation diminishes secretion of Sema4D by osteoclasts, inhibits Sema4D\u2010mediated osteoclast activation, and enhances secretion of Sema3A by osteoblasts, increasing osteoblast differentiation and diminishing inflammatory osteolysis.\u2014Mediero, A., Wilder, T., Shah, L., Cronstein, B.N. Adenosine A\n                    <jats:sub>2A<\/jats:sub>\n                    receptor (A2AR) stimulation modulates expression of semaphorins 4D and 3A, regulators of bone homeostasis. FASEB J. 32, 3487\u20133501 (2018).\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.201700217r","type":"journal-article","created":{"date-parts":[[2018,2,2]],"date-time":"2018-02-02T12:59:04Z","timestamp":1517576344000},"page":"3487-3501","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Adenosine A\n                    <sub>2A<\/sub>\n                    receptor (A2AR) stimulation modulates expression of semaphorins 4D and 3A, regulators of bone homeostasis"],"prefix":"10.1096","volume":"32","author":[{"given":"Ar\u00e1nzazu","family":"Mediero","sequence":"first","affiliation":[{"name":"Division of Translational Medicine Department of Medicine New York University\u2010Langone Medical Center New York New York USA"},{"name":"Bone and Joint Research Unit Instituto de Investigaci\u00f3n Sanitaria de la Fundaci\u00f3n Jim\u00e9nez D\u00edaz\u2010Universidad Aut\u00f3noma de Madrid Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuere","family":"Wilder","sequence":"additional","affiliation":[{"name":"Division of Translational Medicine Department of Medicine New York University\u2010Langone Medical Center New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lopa","family":"Shah","sequence":"additional","affiliation":[{"name":"Division of Translational Medicine Department of Medicine New York University\u2010Langone Medical Center New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce N.","family":"Cronstein","sequence":"additional","affiliation":[{"name":"Division of Translational Medicine Department of Medicine New York University\u2010Langone Medical Center New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,2,2]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-231233"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2012.03.021"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijms.5.263"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2421"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(00)02700-1"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80062-8"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80063-X"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81715-8"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/bonekey.2013.215"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2776(06)93003-X"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nsb977"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2489"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0026627"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/0022034513500306"},{"key":"e_1_2_8_16_1","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.semcdb.2012.09.008","article-title":"Semaphorins in bone development, homeostasis, and disease","volume":"24","author":"Kang S.","year":"2013","journal-title":"Semin. 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