{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T14:05:29Z","timestamp":1753884329938,"version":"3.40.5"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2019,12,6]],"date-time":"2019-12-06T00:00:00Z","timestamp":1575590400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2016M591718"],"award-info":[{"award-number":["2016M591718"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81600836"],"award-info":[{"award-number":["81600836"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Int Endodontic J"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>To analyse the effects of the alternatively spliced fibronectin (FN) gene and its isoforms on osteoclastogenesis in radicular cysts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methodology<\/jats:title><jats:p>Specimens of radicular cysts were collected surgically from 22 patients whose radiolucent periapical areas were measured on digital panoramic radiographs before surgery. The associations between the radiolucent areas and FN isoforms, vascular endothelial growth factor (VEGF) expression or micro\u2010vessel density, as well as the relationships amongst them, were analysed by immunohistochemical staining using the antibodies IST\u20109, BC\u20101, P1F11, VEGF and CD34. Fibroblasts isolated from those specimens were used to induce Trap\u00a0+\u00a0MNCs, and the effects of induction were assessed by blocking FN containing extra domain A (EDA\u00a0+\u00a0FN), COX\u20102 or VEGF <jats:italic>in vitro<\/jats:italic>. The effects of EDA exon knockout using CRISPR\/Cas system were also assessed. Quantitative PCR was used to analyse relative expression of FN isoforms and osteoclastogenic genes. Data were analysed using linear regression, Spearman's rank correlation analysis, chi\u2010square test and Student's <jats:italic>t<\/jats:italic>\u2010test; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05 was considered significant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Micro\u2010vessel density and EDA\u00a0+\u00a0FN staining were positively associated with the size of radiolucent periapical areas (mm<jats:sup>2<\/jats:sup>; <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05), consistent with a positive association between Trap\u00a0+\u00a0MNCs and VEGF expression in fibroblasts (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). Blocking the interaction between EDA\u00a0+\u00a0FN and fibroblasts inhibited Trap\u00a0+\u00a0MNC formation. In addition, EDA exon knockout decreased VEGF expression and inhibited Trap\u00a0+\u00a0MNC formation to the extent of blocking VEGF by bevacizumab, but osteoclastogenic induction was restored by recombinant VEGF. Using retrospective clinicopathological data, VEGF staining was shown to be positively associated with EDA\u00a0+\u00a0FN staining, micro\u2010vessel density and the size of radiolucent areas (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In fibrous capsules of radicular cysts, the alternatively spliced isoform EDA\u00a0+\u00a0FN generated by fibroblasts stimulated VEGF expression via an autocrine effect and then facilitated osteoclastogenesis. Both blockage of VEGF and EDA exon knockout could be used to inhibit bone destruction.<\/jats:p><\/jats:sec>","DOI":"10.1111\/iej.13241","type":"journal-article","created":{"date-parts":[[2019,10,26]],"date-time":"2019-10-26T06:10:07Z","timestamp":1572070207000},"page":"478-491","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The extra domain A of fibronectin facilitates osteoclastogenesis in radicular cysts through vascular endothelial growth factor"],"prefix":"10.1111","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7784-4047","authenticated-orcid":false,"given":"J. 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