{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T18:14:56Z","timestamp":1771006496827,"version":"3.50.1"},"reference-count":45,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2016,4,28]],"date-time":"2016-04-28T00:00:00Z","timestamp":1461801600000},"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","award":["DK34989"],"award-info":[{"award-number":["DK34989"]}],"id":[{"id":"10.13039\/100000002","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":[[2016,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Null mutations in for pigment epithelium\u2010derived factor (PEDF), the protein product of the\n                    <jats:italic>SERPINF1<\/jats:italic>\n                    gene, are the cause of osteogenesis imperfecta (OI) type VI. The PEDF\u2010knockout (KO) mouse captures crucial elements of the human disease, including diminished bone mineralization and propensity to fracture. Our group and others have demonstrated that PEDF directs human mesenchymal stem cell (hMSC) commitment to the osteoblast lineage and modulates Wnt\/\u03b2\u2010catenin signaling, a major regulator of bone development; however, the ability of PEDF to restore bone mass in a mouse model of OI type VI has not been determined. In this study, PEDF delivery increased trabecular bone volume\/total volume by 52% in 6\u2010mo\u2010old PEDF\u2010KO mice but not in wild\u2010type mice. In young (19\u2010d\u2010old) PEDF\u2010KO mice, PEDF restoration increased bone volume fraction by 35% and enhanced biomechanical parameters of bone plasticity. A Wnt\u2010green fluorescent protein reporter demonstrated dynamic changes in Wnt\/\u03b2\u2010catenin signaling characterized by early activation and marked suppression during terminal differentiation of hMSCs. Continuous Wnt3a exposure impeded mineralization of hMSCs, whereas the combination of Wnt3a and PEDF potentiated mineralization. Interrogation of the PEDF sequence identified a conserved motif found in other Wnt modulators, such as the dickkopf proteins. Mutation of a single amino acid on a 34\u2010mer PEDF peptide increased mineralization of hMSC cultures compared with the native peptide sequence. These results indicate that PEDF counters Wnt signaling to allow for osteoblast differentiation and provides a mechanistic insight into how the PEDF null state results in OI type VI.\u2014Belinsky, G. S., Sreekumar, B., Andrejecsk, J. W., Saltzman, W. M., Gong, J., Herzog, R. I., Lin, S., Horsley, V., Carpenter, T. O., Chung, C. Pigment epithelium\u2010derived factor restoration increases bone mass and improves bone plasticity in a model of osteogenesis imperfecta type VI\n                    <jats:italic>via<\/jats:italic>\n                    Wnt3a blockade. FASEB J. 30, 2837\u20102848 (2016).\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.201500027r","type":"journal-article","created":{"date-parts":[[2016,4,29]],"date-time":"2016-04-29T02:12:38Z","timestamp":1461895958000},"page":"2837-2848","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Pigment epithelium\u2010derived factor restoration increases bone mass and improves bone plasticity in a model of osteogenesis imperfecta type VI\n                    <i>via<\/i>\n                    Wnt3a blockade"],"prefix":"10.1096","volume":"30","author":[{"given":"Glenn S.","family":"Belinsky","sequence":"first","affiliation":[{"name":"Department of Medicine Yale University New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bharath","family":"Sreekumar","sequence":"additional","affiliation":[{"name":"Department of Medicine Yale University New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jillian W.","family":"Andrejecsk","sequence":"additional","affiliation":[{"name":"Department of Medicine Yale University New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W. Mark","family":"Saltzman","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Yale University New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingjing","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Medicine Yale University New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raimund I.","family":"Herzog","sequence":"additional","affiliation":[{"name":"Department of Medicine Yale University New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular and Developmental Biology Yale University New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie","family":"Horsley","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular and Developmental Biology Yale University New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas O.","family":"Carpenter","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Yale University School of Medicine Yale University New Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuhan","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Medicine Yale University New Haven Connecticut USA"},{"name":"Veterans Affairs Connecticut Healthcare System West Haven Connecticut USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2016,4,28]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-1505"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)00728-X"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2002.17.1.30"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.487"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.1480"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.01.015"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-1827"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35319"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2012-101142"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2173"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20030313"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1260419"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.1892"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-232900"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.24859"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/stem.1505"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2006.10.010"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01211-10"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2013-1785"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2015.06.006"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2011.07.005"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm870"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.09.065"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2010.01.014"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2004.09.007"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.141"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.08.009"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.20284"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1089\/ten.2006.12.111"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200810137"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28551"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35938"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36481"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1159\/000369108"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.11.139"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2008.12.008"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00252.2009"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1359\/JBMR.050614"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(02)01106-X"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a015081"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2015.11.015"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.06.001"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-2654"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.04-0172"},{"key":"e_1_2_7_46_1","first-page":"11","article-title":"Organization, evolutionary conservation, expression and unusual Alu density of the human gene for pigment epithelium\u2010derived factor, a unique neurotrophic serpin","volume":"2","author":"Tombran\u2010Tink J.","year":"1996","journal-title":"Mol. Vis."}],"updated-by":[{"DOI":"10.1080\/21675511.2016.1212150","type":"addendum","label":"Addendum","source":"publisher","updated":{"date-parts":[[2016,7,19]],"date-time":"2016-07-19T00:00:00Z","timestamp":1468886400000}}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.201500027R","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.201500027R","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.201500027R","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T17:31:48Z","timestamp":1761672708000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.201500027R"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,28]]},"references-count":45,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2016,8]]}},"alternative-id":["10.1096\/fj.201500027R"],"URL":"https:\/\/doi.org\/10.1096\/fj.201500027r","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,4,28]]},"assertion":[{"value":"2015-07-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-04-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-04-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}