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Which are the molecular signals that initiate pattern formation and the induction of bone formation? To evaluate the role of released calcium ions and osteoclastogenesis, 7% <jats:styled-content style=\"fixed-case\">HA<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">CC<\/jats:styled-content> was pre\u2010loaded with either 500\u00a0\u03bcg of the calcium channel blocker, verapamil hydrochloride, or 240\u00a0\u03bcg of the osteoclast inhibitor, biphosphonate zoledronate, and implanted in the <jats:italic>rectus abdominis<\/jats:italic> muscle of six adult <jats:styled-content style=\"fixed-case\">C<\/jats:styled-content>hacma baboons <jats:italic><jats:styled-content style=\"fixed-case\">P<\/jats:styled-content>apio ursinus<\/jats:italic>. Generated tissues on days 15, 60 and 90 were analysed by histomorphometry and <jats:styled-content style=\"fixed-case\">qRT<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">PCR<\/jats:styled-content>. On day 15, up\u2010regulation of <jats:italic>type IV collagen<\/jats:italic> characterized all the implanted constructs correlating with vascular invasion. Zoledronate\u2010treated specimens showed an important delay in tissue patterning and morphogenesis with limited bone formation. Osteoclastic inhibition yielded minimal, if any, bone formation by induction. 7% <jats:styled-content style=\"fixed-case\">HA<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">CC<\/jats:styled-content> pre\u2010loaded with the <jats:styled-content style=\"fixed-case\"><jats:roman>Ca<\/jats:roman><\/jats:styled-content><jats:sup>++<\/jats:sup> channel blocker verapamil hydrochloride strongly inhibited the induction of bone formation. Down\u2010regulation of <jats:italic>bone morphogenetic protein\u20102 (<jats:styled-content style=\"fixed-case\">BMP<\/jats:styled-content>\u20102)<\/jats:italic> together with up\u2010regulation of <jats:italic><jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>oggin<\/jats:italic> genes correlated with limited bone formation in 7% <jats:styled-content style=\"fixed-case\">HA<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">CC<\/jats:styled-content> pre\u2010loaded with either verapamil or zoledronate, indicating that the induction of bone formation by coral\u2010derived macroporous constructs is <jats:italic>via<\/jats:italic> the <jats:styled-content style=\"fixed-case\">BMP<\/jats:styled-content>s pathway. The spontaneous induction of bone formation is initiated by a local peak of <jats:styled-content style=\"fixed-case\"><jats:roman>Ca<\/jats:roman><\/jats:styled-content><jats:sup>++<\/jats:sup> activating stem cell differentiation and the induction of bone formation.<\/jats:p>","DOI":"10.1111\/jcmm.12125","type":"journal-article","created":{"date-parts":[[2013,10,11]],"date-time":"2013-10-11T21:52:36Z","timestamp":1381528356000},"page":"1444-1457","source":"Crossref","is-referenced-by-count":47,"title":["Calcium ions and osteoclastogenesis initiate the induction of bone formation by coral\u2010derived macroporous constructs"],"prefix":"10.1111","volume":"17","author":[{"given":"Roland M","family":"Klar","sequence":"first","affiliation":[{"name":"Bone Research Laboratory School of Physiology Faculty of Health Sciences University of the Witwatersrand Johannesburg South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Duarte","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of the Witwatersrand Johannesburg South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Therese","family":"Dix\u2010Peek","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of the Witwatersrand Johannesburg South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Dickens","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of the Witwatersrand Johannesburg South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Ferretti","sequence":"additional","affiliation":[{"name":"Bone Research Laboratory School of Physiology Faculty of Health Sciences University of the Witwatersrand Johannesburg South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ugo","family":"Ripamonti","sequence":"additional","affiliation":[{"name":"Bone Research Laboratory School of Physiology Faculty of Health Sciences University of the Witwatersrand Johannesburg South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,9,23]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2010.09.048"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1557\/S0883769400031833"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0934-8832(11)80115-0"},{"key":"e_1_2_7_5_1","first-page":"335","article-title":"Sintered porous hydroxyapatites with intrinsic osteoinductive activity: geometric induction of bone formation","volume":"95","author":"Ripamonti U","year":"1999","journal-title":"S Afr J Sci"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2004.tb00272.x"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.prs.0000287133.43718.89"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.041186"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1487"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2010.09.025"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2011.06.063"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2011.09.058"},{"key":"e_1_2_7_13_1","unstructured":"RipamontiU.The concavity: the \u2018shape of life and the control of bone differentiation. 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