{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T17:21:26Z","timestamp":1778001686763,"version":"3.51.4"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T00:00:00Z","timestamp":1588032000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T00:00:00Z","timestamp":1588032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Tissue turnover, especially in the skin, is altered in systemic sclerosis (SSc), leading to tissue accumulation. The objective was to examine type III, IV, and VI collagens turnovers in SSc and investigate longitudinal alterations in relation to modified Rodnan Skin Score (mRSS). We included patients fulfilling the 2013 ACR\/EULAR criteria for SSc (limited cutaneous [lcSSc, n\u2009=\u200920], diffuse cutaneous SSc [dcSSc, n\u2009=\u200923]) and healthy controls (HC, n\u2009=\u200910). Biomarkers of type III, IV, and VI collagens formation (PRO-C3, PRO-C4, PRO-C6) and degradation (C3M, C4M, C6M) were measured in serum. The fibrotic index of the individual collagens (FICol) were calculated. The fibrotic index of type III and VI collagens (FICol3 and FICol6) were increased in dcSSc compared to lcSSc (FICol3: 1.4 vs. 0.8, P\u2009=\u20090.0001; FICol6: 1.2 vs. 0.9, P\u2009=\u20090.03). The fibrotic index of type IV collagen (FICol4) was not different between the groups but was 1.5 times higher than HC (HC: 6.9, lcSSc 10.4, dcSSc: 10.5). Both FICol3 and FICol6 correlated with mRSS with rho\u2019s of 0.59 (P\u2009&lt;\u20090.0001) and 0.35 (P\u2009=\u20090.04). Furthermore, FICol3 steadily decrease over the disease course. Examining collagen turnover and specific collagens could be beneficial in following patients\u2019 skin fibrosis and possibly identifying progressors.<\/jats:p>","DOI":"10.1038\/s41598-020-64233-8","type":"journal-article","created":{"date-parts":[[2020,4,28]],"date-time":"2020-04-28T10:04:21Z","timestamp":1588068261000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Type III, IV, and VI Collagens Turnover in Systemic Sclerosis \u2013 a Longitudinal Study"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7471-8096","authenticated-orcid":false,"given":"Pernille","family":"Juhl","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne-Christine","family":"Bay-Jensen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger","family":"Hesselstrand","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne S.","family":"Siebuhr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dirk M.","family":"Wuttge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,4,28]]},"reference":[{"key":"64233_CR1","doi-asserted-by":"crossref","unstructured":"Allanore, Y. et al. Systemic sclerosis [review]. Nat. Rev. Dis. Prim. 1 (2015).","DOI":"10.1038\/nrdp.2015.2"},{"key":"64233_CR2","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1111\/exd.12673","volume":"24","author":"M Ciechomska","year":"2015","unstructured":"Ciechomska, M., van Laar, J. & O\u2019Reilly, S. Current frontiers in systemic sclerosis pathogenesis. Exp. Dermatol. 24, 401\u2013406 (2015).","journal-title":"Exp. Dermatol."},{"key":"64233_CR3","first-page":"202","volume":"15","author":"EC LeRoy","year":"1988","unstructured":"LeRoy, E. C. et al. Scleroderma (systemic sclerosis): Classification, subsets and pathogenesis [editorial]. J. Rheumatol. 15, 202\u2013205 (1988).","journal-title":"J. Rheumatol."},{"key":"64233_CR4","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/JID.2015.352","volume":"136","author":"G Theocharidis","year":"2016","unstructured":"Theocharidis, G. et al. Type VI Collagen Regulates Dermal Matrix Assembly and Fibroblast Motility. J. Invest. Dermatol. 136, 74\u201383 (2016).","journal-title":"J. Invest. Dermatol."},{"key":"64233_CR5","doi-asserted-by":"publisher","first-page":"1829","DOI":"10.1002\/art.1780331211","volume":"33","author":"J Peltonen","year":"1990","unstructured":"Peltonen, J., Kahari, L., Uitto, J. & Jimenez, S. A. Increased expression of type VI collagen genes in systemic sclerosis. Arthritis Rheum. 33, 1829\u20131835 (1990).","journal-title":"Arthritis Rheum."},{"key":"64233_CR6","first-page":"1","volume":"Dec","author":"P Juhl","year":"2018","unstructured":"Juhl, P. et al. Serum biomarkers of collagen turnover as potential diagnostic tools in diffuse systemic sclerosis: A cross-sectional study. PlosOne Dec, 1\u201312 (2018).","journal-title":"PlosOne"},{"key":"64233_CR7","doi-asserted-by":"publisher","first-page":"1747","DOI":"10.1136\/annrheumdis-2013-204424","volume":"72","author":"F van den Hoogen","year":"2013","unstructured":"van den Hoogen, F. et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology\/European league against rheumatism collaborative initiative. Ann. Rheum. Dis. 72, 1747\u20131755 (2013).","journal-title":"Ann. Rheum. Dis."},{"key":"64233_CR8","doi-asserted-by":"crossref","unstructured":"Wuttge, D. M. et al. Serum IL-15 in patients with early systemic sclerosis: A potential novel marker of lung disease. Arthritis Res. Ther. 9, (2007).","DOI":"10.1186\/ar2284"},{"key":"64233_CR9","first-page":"303","volume":"5","author":"MJ Nielsen","year":"2013","unstructured":"Nielsen, M. J. et al. The neo-epitope specific PRO-C3 ELISA measures true formation of type III collagen associated with liver and muscle parameters. Am. J. Transl. Res. 5, 303\u2013315 (2013).","journal-title":"J. Transl. Res."},{"key":"64233_CR10","doi-asserted-by":"publisher","first-page":"e71050","DOI":"10.1371\/journal.pone.0071050","volume":"8","author":"DJ Leeming","year":"2013","unstructured":"Leeming, D. J., Karsdal, M. A., Rasmussen, L. M., Scholze, A. & Tepel, M. Association of systemic collagen type IV formation with survival among patients undergoing hemodialysis. PLoS One 8, e71050 (2013).","journal-title":"PLoS One"},{"key":"64233_CR11","doi-asserted-by":"publisher","first-page":"e0144525","DOI":"10.1371\/journal.pone.0144525","volume":"10","author":"S Sun","year":"2015","unstructured":"Sun, S. et al. Collagen type III and VI turnover in response to long-term immobilization. PLoS One 10, e0144525 (2015).","journal-title":"PLoS One"},{"key":"64233_CR12","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1016\/j.clinbiochem.2010.03.012","volume":"43","author":"N Barascuk","year":"2010","unstructured":"Barascuk, N. et al. A novel assay for extracellular matrix remodeling associated with liver fibrosis: An enzyme-linked immunosorbent assay (ELISA) for a MMP-9 proteolytically revealed neo-epitope of type III collagen. Clin. Biochem. 43, 899\u2013904 (2010).","journal-title":"Clin. Biochem."},{"key":"64233_CR13","doi-asserted-by":"publisher","first-page":"e84934","DOI":"10.1371\/journal.pone.0084934","volume":"8","author":"JM Sand","year":"2013","unstructured":"Sand, J. M. et al. MMP mediated degradation of type IV collagen alpha 1 and alpha 3 chains reflects basement membrane remodeling in experimental and clinical fibrosis \u2013 validation of two novel biomarker assays. PLoS One 8, e84934 (2013).","journal-title":"PLoS One"},{"key":"64233_CR14","doi-asserted-by":"publisher","first-page":"e24753","DOI":"10.1371\/journal.pone.0024753","volume":"6","author":"SS Veidal","year":"2011","unstructured":"Veidal, S. S. et al. MMP mediated degradation of type VI collagen is highly associated with liver Fibrosis - Identification and validation of a novel biochemical marker assay. PLoS One 6, e24753 (2011).","journal-title":"PLoS One"},{"key":"64233_CR15","doi-asserted-by":"crossref","unstructured":"Wood, S. Generalized Additive Models: An Introduction with R (2nd edition). Chapman and Hall\/CRC. (2017).","DOI":"10.1201\/9781315370279"},{"key":"64233_CR16","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1198\/016214504000000980","volume":"99","author":"SN Wood","year":"2004","unstructured":"Wood, S. N. Stable and efficient multiple smoothing parameter estimation for generalized additive models. J. Am. Stat. Assoc. 99, 673\u2013686 (2004).","journal-title":"J. Am. Stat. Assoc."},{"key":"64233_CR17","unstructured":"Team, R. core. R: A language and environment for statistical computing. R Foundation for Statistical Computing. (2019)."},{"key":"64233_CR18","doi-asserted-by":"publisher","unstructured":"Juhl, P. et al. Association of Metabolites Reflecting Type III and VI Collagen Formation with Modified Rodnan Skin Score in Systemic Sclerosis \u2013 a Cross-sectional Study. Biomarkers 1\u201324, https:\/\/doi.org\/10.1080\/1354750X.2019.1587509 (2019).","DOI":"10.1080\/1354750X.2019.1587509"},{"key":"64233_CR19","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1080\/1354750X.2018.1548032","volume":"24","author":"AS Siebuhr","year":"2019","unstructured":"Siebuhr, A. S. et al. Citrullinated vimentin and biglycan protein fingerprints as candidate serological biomarkers for disease activity in systemic sclerosis: A pilot study. Biomarkers 24, 249\u2013254 (2019).","journal-title":"Biomarkers"},{"key":"64233_CR20","doi-asserted-by":"crossref","unstructured":"Uitto, J., Olsen, D. R. & Fazio, M. J. Extracellular matrix of the skin: 50 years of progress. J. Invest. Dermatol. 92, (1989).","DOI":"10.1111\/1523-1747.ep13075039"},{"key":"64233_CR21","first-page":"1","volume":"4","author":"AMA Velez","year":"2012","unstructured":"Velez, A. M. A. & Howard, M. S. Collagen IV in normal and in disease process. N. Am. J. Med. Sci. 4, 1\u20138 (2012).","journal-title":"J. Med. Sci."},{"key":"64233_CR22","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1097\/MAJ.0000000000000282","volume":"348","author":"M Sebastiani","year":"2014","unstructured":"Sebastiani, M. et al. Measuring microangiopathy abnormalities in systemic sclerosis patients: The role of capillaroscopy-based scoring models. Am. J. Med. Sci. 348, 331\u2013336 (2014).","journal-title":"Am. J. Med. Sci."},{"key":"64233_CR23","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1111\/1346-8138.13564","volume":"44","author":"SI Motegi","year":"2017","unstructured":"Motegi, S. I., Sekiguchi, A., Fujiwara, C., Toki, S. & Ishikawa, O. Possible association of elevated serum collagen type IV level with skin sclerosis in systemic sclerosis. J. Dermatol. 44, 167\u2013172 (2017).","journal-title":"J. Dermatol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64233-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64233-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64233-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T09:48:04Z","timestamp":1670320084000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64233-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,28]]},"references-count":23,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["64233"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-64233-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,28]]},"assertion":[{"value":"24 January 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 April 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 April 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"P.J., A.B., and A.S.S are full-time employees at Nordic Bioscience. Nordic Bioscience is a privately-owned; small-medium size enterprise partly focused on the development of biomarkers for rheumatic and fibrotic diseases. None of the authors received fees, bonuses, or other benefits for the work described in the manuscript. All the other authors declare no conflict of interest. The authors have no other relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7145"}}