{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:48:04Z","timestamp":1787068084197,"version":"build-2736575974"},"reference-count":123,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,8]],"date-time":"2023-07-08T00:00:00Z","timestamp":1688774400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL153195"],"award-info":[{"award-number":["R01 HL153195"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K24 AR060297"],"award-info":[{"award-number":["K24 AR060297"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32 AR050958"],"award-info":[{"award-number":["T32 AR050958"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pulmonary fibrosis (PF) associated with systemic sclerosis (SSc) results in significant morbidity and mortality. We previously reported that insulin-like growth factor-II (IGF-II) is overexpressed in lung tissues and fibroblasts from SSc patients, and IGF-II fosters fibrosis by upregulating collagen type I, fibronectin, and TGF\u03b2. We now show that IGF-II augments mRNA levels of profibrotic signaling molecules TGF\u03b22 (p \u2264 0.01) and TGF\u03b23 (p \u2264 0.05), collagen type III (p \u2264 0.01), and the collagen posttranslational modification enzymes P4HA2 (p \u2264 0.05), P3H2 (p \u2264 0.05), LOX (p = 0.065), LOXL2 (p \u2264 0.05), LOXL4 (p \u2264 0.05) in primary human lung fibroblasts. IGF-II increases protein levels of TGF\u03b22 (p \u2264 0.01), as well as COL3A1, P4HA2, P4H\u03b2, and LOXL4 (p \u2264 0.05). In contrast, IGF-II decreases mRNA levels of the collagen degradation enzymes cathepsin (CTS) K, CTSB, and CTSL and protein levels of CTSK (p \u2264 0.05). The SRY-box transcription factor 9 (SOX9) is overexpressed in SSc lung tissues at the mRNA (p \u2264 0.05) and protein (p \u2264 0.01) levels compared to healthy controls. IGF-II induces SOX9 in lung fibroblasts (p \u2264 0.05) via the IGF1R\/IR hybrid receptor, and SOX9 regulates TGF\u03b22 (p \u2264 0.05), TGF\u03b23 (p \u2264 0.05), COL3A1 (p \u2264 0.01), and P4HA2 (p \u2264 0.001) downstream of IGF-II. Our results identify a novel IGF-II signaling axis and downstream targets that are regulated in a SOX9-dependent and -independent manner. Our findings provide novel insights on the role of IGF-II in promoting pulmonary fibrosis.<\/jats:p>","DOI":"10.3390\/ijms241411234","type":"journal-article","created":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T00:35:21Z","timestamp":1688949321000},"page":"11234","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["The Role of SOX9 in IGF-II-Mediated Pulmonary Fibrosis"],"prefix":"10.3390","volume":"24","author":[{"given":"Kristy M.","family":"Waldrep","sequence":"first","affiliation":[{"name":"Department of Medicine, Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessalyn I.","family":"Rodgers","sequence":"additional","affiliation":[{"name":"Department of Medicine, Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9220-0947","authenticated-orcid":false,"given":"Sara M.","family":"Garrett","sequence":"additional","affiliation":[{"name":"Department of Medicine, Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7124-5158","authenticated-orcid":false,"given":"Bethany J.","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department of Public Health Sciences, Biostatistics and Bioinformatics, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6750-6407","authenticated-orcid":false,"given":"Carol A.","family":"Feghali-Bostwick","sequence":"additional","affiliation":[{"name":"Department of Medicine, Rheumatology, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1755-1536-5-11","article-title":"Molecular and Cellular Mechanisms of Pulmonary Fibrosis","volume":"5","author":"Todd","year":"2012","journal-title":"Fibrogenesis Tissue Repair"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1136\/ard.2006.066068","article-title":"Changes in Causes of Death in Systemic Sclerosis, 1972\u20132002","volume":"66","author":"Steen","year":"2007","journal-title":"Ann. 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