{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T18:43:58Z","timestamp":1784227438094,"version":"3.55.0"},"reference-count":43,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T00:00:00Z","timestamp":1672876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002301","name":"Estonian Research Council","doi-asserted-by":"publisher","award":["PRG057"],"award-info":[{"award-number":["PRG057"]}],"id":[{"id":"10.13039\/501100002301","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002301","name":"Estonian Research Council","doi-asserted-by":"publisher","award":["PSG737"],"award-info":[{"award-number":["PSG737"]}],"id":[{"id":"10.13039\/501100002301","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dupuytren\u2019s contracture (DC) is a chronic and progressive fibroproliferative disorder restricted to the palmar fascia of the hands. Previously, we discovered the presence of high levels of connective tissue growth factor in sweat glands in the vicinity of DC nodules and hypothesized that sweat glands have an important role in the formation of DC lesions. Here, we shed light on the role of sweat glands in the DC pathogenesis by proteomic analysis and immunofluorescence microscopy. We demonstrated that a fraction of sweat gland epithelium underwent epithelial-mesenchymal transition illustrated by negative regulation of E-cadherin. We hypothesized that the increase in connective tissue growth factor expression in DC sweat glands has both autocrine and paracrine effects in sustaining the DC formation and inducing pathological changes in DC-associated sweat glands.<\/jats:p>","DOI":"10.3390\/ijms24021081","type":"journal-article","created":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T01:48:19Z","timestamp":1672969699000},"page":"1081","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Proteomic Analysis of Dupuytren\u2019s Contracture-Derived Sweat Glands Revealed the Synthesis of Connective Tissue Growth Factor and Initiation of Epithelial-Mesenchymal Transition as Major Pathogenetic Events"],"prefix":"10.3390","volume":"24","author":[{"given":"Claudia Griselda","family":"C\u00e1rdenas-Le\u00f3n","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"M\u00e4emets-Allas","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2457-5928","authenticated-orcid":false,"given":"Mariliis","family":"Klaas","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9428-0116","authenticated-orcid":false,"given":"Katre","family":"Maasalu","sequence":"additional","affiliation":[{"name":"Department of Traumatology and Orthopedics, Institute of Clinical Medicine, University of Tartu, 51010 Tartu, Estonia"},{"name":"Clinic of Traumatology and Orthopedics, Tartu University Hospital, 51010 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2221-6262","authenticated-orcid":false,"given":"Viljar","family":"Jaks","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, 51010 Tartu, Estonia"},{"name":"Dermatology Clinic, Tartu University Clinics, 50411 Tartu, Estonia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.jid.2021.05.030","article-title":"Deciphering Mesenchymal Drivers of Human Dupuytren\u2019s Disease at Single-Cell Level","volume":"142","author":"Dobie","year":"2022","journal-title":"J. Investig. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Samulenas, G., Insodaite, R., Kunceviciene, E., Poceviciute, R., Masionyte, L., Zitkeviciute, U., Pilipaityte, L., and Smalinskiene, A. (2022). The Role of Functional Polymorphisms in the Extracellular Matrix Modulation-Related Genes on Dupuytren\u2019s Contracture. Genes, 13.","DOI":"10.3390\/genes13050743"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"14669","DOI":"10.1038\/s41598-021-94025-7","article-title":"Metabolic factors and the risk of Dupuytren\u2019s disease: Data from 30,000 individuals followed for over 20 years","volume":"11","author":"Rydberg","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1097\/PRS.0b013e3182958a33","article-title":"Prevalence of Dupuytren disease in The Netherlands","volume":"132","author":"Lanting","year":"2013","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1111\/cge.12410","article-title":"The importance of genetic susceptibility in Dupuytren\u2019s disease","volume":"87","author":"Becker","year":"2015","journal-title":"Clin. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"20753","DOI":"10.1073\/pnas.2004281117","article-title":"Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP\/EP300","volume":"117","author":"Williams","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1186\/s13075-015-0661-y","article-title":"Laminin-rich blood vessels display activated growth factor signaling and act as the proliferation centers in Dupuytren\u2019s contracture","volume":"17","author":"Viil","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"997","DOI":"10.3892\/ijmm.2014.1851","article-title":"Isolation, culture and phenotypic characterization of human sweat gland epithelial cells","volume":"34","author":"Gao","year":"2014","journal-title":"Int. J. Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"tkac011","DOI":"10.1093\/burnst\/tkac011","article-title":"Epithelial-mesenchymal transition in organ fibrosis development: Current understanding and treatment strategies","volume":"10","author":"Liu","year":"2022","journal-title":"Burns Trauma"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.acthis.2015.03.004","article-title":"Combination of keratins and alpha-smooth muscle actin distinguishes secretory coils from ducts of eccrine sweat glands","volume":"117","author":"Li","year":"2015","journal-title":"Acta Histochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s12079-016-0331-0","article-title":"Update on the role of molecular factors and fibroblasts in the pathogenesis of Dupuytren\u2019s disease","volume":"10","author":"Tripoli","year":"2016","journal-title":"J. Cell Commun. Signal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"13940","DOI":"10.1038\/s41598-022-18116-9","article-title":"Verteporfin ameliorates fibrotic aspects of Dupuytren\u2019s disease nodular fibroblasts irrespective the activation state of the cells","volume":"12","author":"Riesmeijer","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"667765","DOI":"10.3389\/fcell.2021.667765","article-title":"Eccrine Sweat Gland and Its Regeneration: Current Status and Future Directions","volume":"9","author":"Lin","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/s41419-019-1485-5","article-title":"Sweat gland organoids contribute to cutaneous wound healing and sweat gland regeneration","volume":"10","author":"Diao","year":"2019","journal-title":"Cell Death. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Leung, Y., Kandyba, E., Chen, Y.B., Ruffins, S., and Kobielak, K. (2013). Label retaining cells (LRCs) with myoepithelial characteristic from the proximal acinar region define stem cells in the sweat gland. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0074174"},{"key":"ref_16","first-page":"2164","article-title":"Connective tissue growth factor causes EMT-like cell fate changes in vivo and in vitro","volume":"126","author":"Sonnylal","year":"2013","journal-title":"J. Cell Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1016\/j.cellsig.2013.05.027","article-title":"Transforming growth factor \u03b2 induces expression of connective tissue growth factor in hepatic progenitor cells through Smad independent signaling","volume":"25","author":"Ding","year":"2013","journal-title":"Cell. Signal."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Cheng, J.C., Chang, H.M., Fang, L., Sun, Y.P., and Leung, P.C. (2015). TGF-\u03b21 Up-Regulates Connective Tissue Growth Factor Expression in Human Granulosa Cells through Smad and ERK1\/2 Signaling Pathways. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0126532"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1002\/art.27445","article-title":"Regulation of CCN2\/connective tissue growth factor expression in the nucleus pulposus of the intervertebral disc: Role of Smad and activator protein 1 signaling","volume":"62","author":"Tran","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"30708","DOI":"10.1074\/jbc.M113.478685","article-title":"Transforming growth factor-\u03b2 (TGF-\u03b2)-mediated connective tissue growth factor (CTGF) expression in hepatic stellate cells requires Stat3 signaling activation","volume":"288","author":"Liu","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1111\/j.1523-1755.2002.kid567.x","article-title":"CTGF expression in mesangial cells: Involvement of SMADs, MAP kinase, and PKC","volume":"62","author":"Chen","year":"2002","journal-title":"Kidney Int."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Loh, C.Y., Chai, J.Y., Tang, T.F., Wong, W.F., Sethi, G., Shanmugam, M.K., Chong, P.P., and Looi, C.Y. (2019). The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges. Cells, 8.","DOI":"10.3390\/cells8101118"},{"key":"ref_23","first-page":"61","article-title":"Holding Tight: Cell Junctions and Cancer Spread","volume":"8","author":"Knights","year":"2012","journal-title":"Trends Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1053\/hupa.2001.26463","article-title":"Co-downregulation of cell adhesion proteins alpha- and beta-catenins, p120CTN, E-cadherin, and CD44 in prostatic adenocarcinomas","volume":"32","author":"Kallakury","year":"2001","journal-title":"Hum. Pathol."},{"key":"ref_25","first-page":"1","article-title":"Ras suppressor-1 (RSU1) exerts a tumor suppressive role with prognostic significance in lung adenocarcinoma","volume":"2022","author":"Nikou","year":"2022","journal-title":"Clin. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/j.1582-4934.2011.01419.x","article-title":"aV integrins and TGF-\u03b2-induced EMT: A circle of regulation","volume":"16","author":"Mamuya","year":"2012","journal-title":"J. Cell. Mol. Med."},{"key":"ref_27","first-page":"8","article-title":"Inhibition of RhoA\/Rho-kinase pathway suppresses the expression of extracellular matrix induced by CTGF or TGF-\u03b2 in ARPE-19","volume":"6","author":"Zhu","year":"2013","journal-title":"Int. J. Ophthalmol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1111\/1346-8138.12235","article-title":"Epithelial-mesenchymal transition of the eccrine glands is involved in skin fibrosis in morphea","volume":"40","author":"Takahashi","year":"2013","journal-title":"J. Dermatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e15437","DOI":"10.1111\/dth.15437","article-title":"Janus kinase inhibitors for treatment of morphea and systemic sclerosis: A literature review","volume":"35","author":"McGaugh","year":"2022","journal-title":"Dermatol. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e1138","DOI":"10.1097\/GOX.0000000000001138","article-title":"Examination of Epithelial Mesenchymal Transition in Keloid Tissues and Possibility of Keloid Therapy Target","volume":"4","author":"Kuwahara","year":"2016","journal-title":"Plast. Reconstr. Surg. Glob. Open"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"607483","DOI":"10.3389\/fcell.2020.607483","article-title":"The Epithelial-to-Mesenchymal Transition as a Possible Therapeutic Target in Fibrotic Disorders","volume":"8","author":"Robuffo","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e1064","DOI":"10.1097\/GOX.0000000000001064","article-title":"Embryonic Stem Cell-like Population in Dupuytren\u2019s Disease","volume":"4","author":"Koh","year":"2016","journal-title":"Plast. Reconstr. Surg. Glob. Open"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Alfonso-Rodr\u00edguez, C.A., Garz\u00f3n, I., Garrido-G\u00f3mez, J., Oliveira, A.C., Mart\u00edn-Piedra, M., Scionti, G., Carriel, V., Hern\u00e1ndez-Cort\u00e9s, P., Campos, A., and Alaminos, M. (2014). Identification of histological patterns in clinically affected and unaffected palm regions in dupuytren\u2019s disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0112457"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1089\/dna.1992.11.511","article-title":"cDNA cloning and sequence analysis of beta ig-h3, a novel gene induced in a human adenocarcinoma cell line after treatment with transforming growth factor-beta","volume":"11","author":"Skonier","year":"1992","journal-title":"DNA Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"F1026","DOI":"10.1152\/ajprenal.00038.2017","article-title":"Deletion of \u03b21-integrin in collecting duct principal cells leads to tubular injury and renal medullary fibrosis","volume":"313","author":"Mamuya","year":"2017","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Schwanekamp, J.A., Lorts, A., Sargent, M.A., York, A.J., Grimes, K.M., Fischesser, D.M., Gokey, J.J., Whitsett, J.A., Conway, S.J., and Molkentin, J.D. (2017). TGFBI functions similar to periostin but is uniquely dispensable during cardiac injury. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181945"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"22023","DOI":"10.18632\/oncotarget.25153","article-title":"Periostin, a signal transduction intermediate in TGF-\u03b2-induced EMT in U-87MG human glioblastoma cells, and its inhibition by anthocyanidins","volume":"9","author":"Ouanouki","year":"2018","journal-title":"Oncotarget"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"469","DOI":"10.3109\/03008207.2012.686542","article-title":"Expression of MMP-2, TIMP-2, TGF-\u03b21, and decorin in Dupuytren\u2019s contracture","volume":"53","author":"Gosk","year":"2012","journal-title":"Connect. Tissue Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/S0363-5023(96)80102-X","article-title":"The role of transforming growth factor beta in Dupuytren\u2019s disease","volume":"21","author":"Badalamente","year":"1996","journal-title":"J. Hand Surg."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1111\/ics.12769","article-title":"A novel cell line from human eccrine sweat gland duct cells for investigating sweating physiology","volume":"44","author":"Welzel","year":"2022","journal-title":"Int. J. Cosmet. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"113111","DOI":"10.1016\/j.yexcr.2022.113111","article-title":"Olfactomedin 4 regulates migration and proliferation of immortalized non-transformed keratinocytes through modulation of the cell cycle machinery and actin cytoskeleton remodelling","volume":"415","author":"Klaas","year":"2022","journal-title":"Exp. Cell Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41592-019-0638-x","article-title":"DIA-NN: Neural networks and interference correction enable deep proteome coverage in high throughput","volume":"17","author":"Demichev","year":"2020","journal-title":"Nat. Methods"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/nmeth.3901","article-title":"The Perseus computational platform for comprehensive analysis of (prote)omics data","volume":"13","author":"Tyanova","year":"2016","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/2\/1081\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:00:45Z","timestamp":1760119245000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/2\/1081"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,5]]},"references-count":43,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["ijms24021081"],"URL":"https:\/\/doi.org\/10.3390\/ijms24021081","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,5]]}}}