{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:21:57Z","timestamp":1791350517080,"version":"4.3.1"},"reference-count":51,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2011,8,24]],"date-time":"2011-08-24T00:00:00Z","timestamp":1314144000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genesis"],"published-print":{"date-parts":[[2011,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Much is known regarding the role of Indian hedgehog (<jats:italic>Ihh<\/jats:italic>) in endochondral ossification, where <jats:italic>Ihh<\/jats:italic> regulates multiple steps of chondrocyte differentiation. The <jats:italic>Ihh<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> phenotype is most notable for severely foreshortened limbs and a complete absence of mature osteoblasts. A far less explored phenotype in the <jats:italic>Ihh<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mutant is found in the calvaria, where bones form predominately through intramembranous ossification. We investigated the role of <jats:italic>Ihh<\/jats:italic> in calvarial bone ossification, finding that proliferation was largely unaffected. Instead, our results indicate that <jats:italic>Ihh<\/jats:italic> is a pro\u2010osteogenic factor that positively regulates intramembranous ossification. We confirmed through histologic and quantitative gene analysis that loss of <jats:italic>Ihh<\/jats:italic> results in reduction of cranial bone size and all markers of osteodifferentiation. Moreover, in vitro studies suggest that <jats:italic>Ihh<\/jats:italic> loss reduces <jats:italic>Bmp<\/jats:italic> expression within the calvaria, an observation that may underlie the <jats:italic>Ihh<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> calvarial phenotype. In conjunction with the newly recognized roles of Hedgehog deregulation in craniosynostosis, our study defines <jats:italic>Ihh<\/jats:italic> as an important positive regulator of cranial bone ossification. genesis 49:784\u2013796, 2011. \u00a9 2011 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/dvg.20768","type":"journal-article","created":{"date-parts":[[2011,5,6]],"date-time":"2011-05-06T17:26:16Z","timestamp":1304702776000},"page":"784-796","source":"Crossref","is-referenced-by-count":81,"title":["Indian hedgehog positively regulates calvarial ossification and modulates bone morphogenetic protein signaling"],"prefix":"10.1002","volume":"49","author":[{"given":"Kelly","family":"Lenton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron W.","family":"James","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Manu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha A.","family":"Brugmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Birker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily R.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Leucht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill A.","family":"Helms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Longaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,8,24]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.002709"},{"key":"e_1_2_5_3_1","first-page":"23","volume-title":"Molecular and cellular methods in developmental toxicology","author":"Albrecht UEG","year":"1997"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/368208a0"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1995.0010"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.22.13030"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI11706"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01649"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2004.01.011"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.277.5329.1109"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbm.a.31355"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.1998.tb02648.x"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90379-5"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.sap.0000232833.41739.a5"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1089\/ten.tea.2010.0048"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/PRS.0b013e31817747b5"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S8756-3282(03)00092-9"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1086\/518047"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2008.11.010"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2443.1999.00250.x"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.23.9055-9067.2000"},{"key":"e_1_2_5_22_1","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1242\/dev.125.7.1241","article-title":"FGF, BMP, and Shh mediated signaling pathways in the regulation of cranial suture morphogenesis and calvarial bone development","volume":"125","author":"Kim H","year":"1998","journal-title":"Development"},{"key":"e_1_2_5_23_1","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1242\/dev.129.12.2977","article-title":"PTHrP and Indian hedgehog control differentiation of growth plate chondrocytes at multiple steps","volume":"129","author":"Kobayashi T","year":"2002","journal-title":"Development (Cambridge, England)"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.142.2.940"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/0470846658.ch10"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2007.08.028"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.273.5275.663"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1089\/scd.2010.0250"},{"key":"e_1_2_5_29_1","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.1242\/dev.128.24.5099","article-title":"Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation","volume":"128","author":"Long F","year":"2001","journal-title":"Development (Cambridge, England)"},{"key":"e_1_2_5_30_1","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1242\/dev.124.6.1109","article-title":"Role of BMP\u20102 and OP\u20101 (BMP\u20107) in programmed cell death and skeletogenesis during chick limb development","volume":"124","author":"Macias D","year":"1997","journal-title":"Development (Cambridge, England)"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.018044"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420220306"},{"key":"e_1_2_5_33_1","doi-asserted-by":"crossref","first-page":"4523","DOI":"10.1242\/dev.128.22.4523","article-title":"BMP and Ihh\/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation","volume":"128","author":"Minina E","year":"2001","journal-title":"Development (Cambridge, England)"},{"key":"e_1_2_5_34_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1997.7156"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1998.9181"},{"key":"e_1_2_5_36_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.029926"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1159\/isbn.978-3-8055-8152-3"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq258"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.114.11.2085"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.16.2072"},{"key":"e_1_2_5_41_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.028605"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2003.07.004"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.273.5275.613"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4773(97)00203-7"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01545"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.10.1647"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2004.06.010"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1097\/PRS.0b013e31818cbf44"},{"key":"e_1_2_5_49_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.prs.0000279491.48283.51"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2006.07.028"},{"key":"e_1_2_5_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.10166"},{"key":"e_1_2_5_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-8-12"}],"container-title":["genesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fdvg.20768","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/dvg.20768","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T14:35:31Z","timestamp":1700490931000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/dvg.20768"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,8,24]]},"references-count":51,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2011,10]]}},"alternative-id":["10.1002\/dvg.20768"],"URL":"https:\/\/doi.org\/10.1002\/dvg.20768","archive":["Portico"],"relation":{},"ISSN":["1526-954X","1526-968X"],"issn-type":[{"value":"1526-954X","type":"print"},{"value":"1526-968X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,8,24]]}}}