{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T07:43:23Z","timestamp":1762674203345},"reference-count":35,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2018,9,28]],"date-time":"2018-09-28T00:00:00Z","timestamp":1538092800000},"content-version":"am","delay-in-days":316,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#am"},{"start":{"date-parts":[[2017,11,16]],"date-time":"2017-11-16T00:00:00Z","timestamp":1510790400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["W81XWH\u201012\u20102\u20100118","W81XWH\u201012\u20102\u20100119","W81XWH\u201012\u20102\u20100120"],"award-info":[{"award-number":["W81XWH\u201012\u20102\u20100118","W81XWH\u201012\u20102\u20100119","W81XWH\u201012\u20102\u20100120"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Orthopaedic Research"],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:label \/><jats:p>Heterotopic ossification (HO) develops in the extremities of wounded service members and is common in the setting of high\u2010energy penetrating injuries and blast\u2010related amputations. No safe and effective prophylaxis modality has been identified for this patient population. Palovarotene has been shown to reduce bone formation in traumatic and genetic models of HO. The purpose of this study was to determine the effects of Palovarotene on inflammation, progenitor cell proliferation, and gene expression following a blast\u2010related amputation in a rodent model (<jats:italic>n<\/jats:italic>\u2009=\u200972 animals), as well as the ability of Raman spectroscopy to detect early HO before radiographic changes are present. Treatment with Palovarotene was found to dampen the systemic inflammatory response including the cytokines IL\u20106 (<jats:italic>p<\/jats:italic>\u2009=\u20090.01), TNF\u2010\u03b1 (<jats:italic>p<\/jats:italic>\u2009=\u20090.001), and IFN\u2010\u03b3 (<jats:italic>p<\/jats:italic>\u2009=\u20090.03) as well as the local inflammatory response via a 76% reduction in the cellular infiltration at post\u2010operative day (POD)\u20107 (<jats:italic>p<\/jats:italic>\u2009=\u20090.03). Palovarotene decreased osteogenic connective tissue progenitor (CTP\u2010O) colonies by as much as 98% both in vitro (<jats:italic>p<\/jats:italic>\u2009=\u20090.04) and in vivo (<jats:italic>p<\/jats:italic>\u2009=\u20090.01). Palovarotene treated animals exhibited significantly decreased expression of osteo\u2010 and chondrogenic genes by POD\u20107, including BMP4 (<jats:italic>p<\/jats:italic>\u2009=\u20090.02). Finally, Raman spectroscopy was able to detect differences between the two groups by POD\u20101 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). These results indicate that Palovarotene inhibits traumatic HO formation through multiple inter\u2010related mechanisms including anti\u2010inflammatory, anti\u2010proliferative, and gene expression modulation. Further, that Raman spectroscopy is able to detect markers of early HO formation before it becomes radiographically evident, which could facilitate earlier diagnosis and treatment. \u00a9 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1135\u20131144, 2018.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jor.23747","type":"journal-article","created":{"date-parts":[[2017,9,28]],"date-time":"2017-09-28T15:51:22Z","timestamp":1506613882000},"page":"1135-1144","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Palovarotene inhibits connective tissue progenitor cell proliferation in a rat model of combat\u2010related heterotopic ossification"],"prefix":"10.1002","volume":"36","author":[{"given":"Benjamin M.","family":"Wheatley","sequence":"first","affiliation":[{"name":"Regenerative Medicine Department Naval Medical Research Center Silver Spring Maryland"},{"name":"Orthopaedics Uniformed Services University\u2010Walter Reed Department of Surgery Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine E.","family":"Cilwa","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Department Naval Medical Research Center Silver Spring Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devaveena","family":"Dey","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Department Naval Medical Research Center Silver Spring Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ammar T.","family":"Qureshi","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Department Naval Medical Research Center Silver Spring Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan G.","family":"Seavey","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Department Naval Medical Research Center Silver Spring Maryland"},{"name":"Orthopaedics Uniformed Services University\u2010Walter Reed Department of Surgery Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allison M.","family":"Tomasino","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Department Naval Medical Research Center Silver Spring Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin M.","family":"Sanders","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Department Naval Medical Research Center Silver Spring Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wesley","family":"Bova","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Cleveland Clinic Cleveland Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cynthia A.","family":"Boehm","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Cleveland Clinic Cleveland Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiro","family":"Iwamoto","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics University of Maryland Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin K.","family":"Potter","sequence":"additional","affiliation":[{"name":"Orthopaedics Uniformed Services University\u2010Walter Reed Department of Surgery Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan A.","family":"Forsberg","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Department Naval Medical Research Center Silver Spring Maryland"},{"name":"Orthopaedics Uniformed Services University\u2010Walter Reed Department of Surgery Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George F.","family":"Muschler","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Cleveland Clinic Cleveland Ohio"},{"name":"Department of Orthopaedic Surgery Cleveland Clinic Cleveland Ohio"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas A.","family":"Davis","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Department Naval Medical Research Center Silver Spring Maryland"},{"name":"Orthopaedics Uniformed Services University\u2010Walter Reed Department of Surgery Bethesda Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,11,16]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.2106\/00004623-200703000-00003"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.2106\/JBJS.H.00792"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOT.0b013e3182703188"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.2106\/JBJS.J.00257"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOT.0b013e3182a53130"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.5435\/00124635-200600001-00042"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11999-015-4266-1"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00256-005-0958-z"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2010.122"},{"key":"e_1_2_7_11_1","first-page":"1281","article-title":"Molecular and cellular mechanisms of heterotopic ossification","volume":"29","author":"Ramirez D","year":"2014","journal-title":"Histol Histopathol"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1302\/0301-620X.97B4.34866"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/SLA.0b013e3181b248d9"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11999-014-3694-7"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOT.0b013e31825d60a5"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.148.4.679"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200112029"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200604150"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/jor.20985"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2820"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2334"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2016.06.014"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-15-0038"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2017.01.004"},{"key":"e_1_2_7_25_1","first-page":"172","article-title":"Prophylactic administration of all\u2010trans retinoic acid alleviates inflammation in rats with collagen\u2010induced arthritis","volume":"37","author":"Zeng X","year":"2016","journal-title":"Nan Fang Yi Ke Da Xue Xue Bao"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11999-015-4240-y"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2013.01.002"},{"key":"e_1_2_7_28_1","doi-asserted-by":"crossref","unstructured":"CilwaK QureshiA ForsbergJ et al. Determining early markers of disease using Raman spectroscopy in a rat combat\u2010trauma model of heterotopic ossification. Proc SPIE 9689 Photonic Therapeutics and Diagnostics XII 96894G. (February 29 2016).","DOI":"10.1117\/12.2213334"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.3109\/03008207.2015.1013190"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11999-015-4272-3"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2795(79)90118-1"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1039\/c0an00459f"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2013.08.026"},{"key":"e_1_2_7_34_1","unstructured":"PerkashA.Persistent hypercoagulation associated with heterotopic ossification in patients with spinal cord injury long after injury has occurred2017. Available from:https:\/\/www.ncbi.nlm.nih.gov\/pubmed\/."},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.sc.3101309"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI84059"}],"container-title":["Journal of Orthopaedic Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjor.23747","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jor.23747","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jor.23747","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/am-pdf\/10.1002\/jor.23747","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jor.23747","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,24]],"date-time":"2023-09-24T13:24:00Z","timestamp":1695561840000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jor.23747"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,16]]},"references-count":35,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2018,4]]}},"alternative-id":["10.1002\/jor.23747"],"URL":"https:\/\/doi.org\/10.1002\/jor.23747","archive":["Portico"],"relation":{},"ISSN":["0736-0266","1554-527X"],"issn-type":[{"value":"0736-0266","type":"print"},{"value":"1554-527X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,16]]},"assertion":[{"value":"2017-06-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-09-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-11-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}