{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:28:08Z","timestamp":1791325688653,"version":"4.3.1"},"reference-count":42,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T00:00:00Z","timestamp":1581379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CURE CMD","award":["Exploring the involvement of ColVI-NG2 axis in the generation of contractures affecting UCMD patients"],"award-info":[{"award-number":["Exploring the involvement of ColVI-NG2 axis in the generation of contractures affecting UCMD patients"]}]},{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["2015FBNB5Y  201742SBXA"],"award-info":[{"award-number":["2015FBNB5Y  201742SBXA"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Mutations in collagen VI genes cause two major clinical myopathies, Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD), and the rarer myosclerosis myopathy. In addition to congenital muscle weakness, patients affected by collagen VI-related myopathies show axial and proximal joint contractures, and distal joint hypermobility, which suggest the involvement of tendon function. To gain further insight into the role of collagen VI in human tendon structure and function, we performed ultrastructural, biochemical, and RT-PCR analysis on tendon biopsies and on cell cultures derived from two patients affected with BM and UCMD. In vitro studies revealed striking alterations in the collagen VI network, associated with disruption of the collagen VI-NG2 (Collagen VI-neural\/glial antigen 2) axis and defects in cell polarization and migration. The organization of extracellular matrix (ECM) components, as regards collagens I and XII, was also affected, along with an increase in the active form of metalloproteinase 2 (MMP2). In agreement with the in vitro alterations, tendon biopsies from collagen VI-related myopathy patients displayed striking changes in collagen fibril morphology and cell death. These data point to a critical role of collagen VI in tendon matrix organization and cell behavior. The remodeling of the tendon matrix may contribute to the muscle dysfunction observed in BM and UCMD patients.<\/jats:p>","DOI":"10.3390\/cells9020409","type":"journal-article","created":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T11:45:30Z","timestamp":1581421530000},"page":"409","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Tendon Extracellular Matrix Remodeling and Defective Cell Polarization in the Presence of Collagen VI Mutations"],"prefix":"10.3390","volume":"9","author":[{"given":"Manuela","family":"Antoniel","sequence":"first","affiliation":[{"name":"CNR-Institute of Molecular Genetics \u201cLuigi Luca Cavalli-Sforza\u201d-Unit of Bologna, 40136 Bologna, Italy"},{"name":"IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0196-101X","authenticated-orcid":false,"given":"Francesco","family":"Traina","sequence":"additional","affiliation":[{"name":"Ortopedia-Traumatologia e Chirurgia Protesica e dei Reimpianti d\u2019Anca e di Ginocchio, Istituto Ortopedico Rizzoli di Bologna, 40136 Bologna, Italy"},{"name":"Dipartimento di Scienze Biomediche, Odontoiatriche e delle Immagini Morfologiche e Funzionali, Universit\u00e0 Degli Studi Di Messina, 98122 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1108-1198","authenticated-orcid":false,"given":"Luciano","family":"Merlini","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences, University of Bologna, 40123 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Andrenacci","sequence":"additional","affiliation":[{"name":"CNR-Institute of Molecular Genetics \u201cLuigi Luca Cavalli-Sforza\u201d-Unit of Bologna, 40136 Bologna, Italy"},{"name":"IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Tigani","sequence":"additional","affiliation":[{"name":"Department of Orthopedic and Trauma Surgery, Ospedale Maggiore, 40133 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spartaco","family":"Santi","sequence":"additional","affiliation":[{"name":"CNR-Institute of Molecular Genetics \u201cLuigi Luca Cavalli-Sforza\u201d-Unit of Bologna, 40136 Bologna, Italy"},{"name":"IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8062-1840","authenticated-orcid":false,"given":"Vittoria","family":"Cenni","sequence":"additional","affiliation":[{"name":"CNR-Institute of Molecular Genetics \u201cLuigi Luca Cavalli-Sforza\u201d-Unit of Bologna, 40136 Bologna, Italy"},{"name":"IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Sabatelli","sequence":"additional","affiliation":[{"name":"CNR-Institute of Molecular Genetics \u201cLuigi Luca Cavalli-Sforza\u201d-Unit of Bologna, 40136 Bologna, Italy"},{"name":"IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesare","family":"Faldini","sequence":"additional","affiliation":[{"name":"1st Orthopaedic and Traumatologic Clinic, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6538-5923","authenticated-orcid":false,"given":"Stefano","family":"Squarzoni","sequence":"additional","affiliation":[{"name":"CNR-Institute of Molecular Genetics \u201cLuigi Luca Cavalli-Sforza\u201d-Unit of Bologna, 40136 Bologna, Italy"},{"name":"IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1136\/jmg.2002.002311","article-title":"Collagen VI related muscle disorders","volume":"42","author":"Lampe","year":"2005","journal-title":"J. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj3160001","article-title":"Collagen fibril formation","volume":"316","author":"Kadler","year":"1996","journal-title":"Biochem. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1002\/jor.22818","article-title":"Tendon functional extracellular matrix","volume":"33","author":"Screen","year":"2015","journal-title":"J. Orthop. Res. Off. Publ. Orthop. Res. Soc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1016\/S0969-2126(03)00181-3","article-title":"Tendon cell array isolation reveals a previously unknown fibrillin-2-containing macromolecular assembly","volume":"11","author":"Ritty","year":"2003","journal-title":"Structure"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2","DOI":"10.3109\/03008207.2011.602766","article-title":"Pericellular proteins of the developing mouse tendon: A proteomic analysis","volume":"53","author":"Smith","year":"2012","journal-title":"Connect. Tissue Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1083\/jcb.103.2.393","article-title":"Type VI collagen in extracellular, 100-nm periodic filaments and fibrils: Identification by immunoelectron microscopy","volume":"103","author":"Bruns","year":"1986","journal-title":"J. Cell Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1111\/j.1432-1033.1984.tb08313.x","article-title":"Immunochemistry, genuine size and tissue localization of collagen VI","volume":"142","author":"Aumailley","year":"1984","journal-title":"Eur. J. Biochem. FEBS"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"49120","DOI":"10.1074\/jbc.M206891200","article-title":"Biglycan organizes collagen VI into hexagonal-like networks resembling tissue structures","volume":"277","author":"Wiberg","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.jsb.2006.03.023","article-title":"Structural correlation between collagen VI microfibrils and collagen VI banded aggregates","volume":"154","author":"Knupp","year":"2006","journal-title":"J. Struct. Biol."},{"key":"ref_10","first-page":"638","article-title":"Three-dimensional architecture of collagen type VI in the human trabecular meshwork","volume":"20","author":"Koudouna","year":"2014","journal-title":"Mol. Vis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"20170","DOI":"10.1074\/jbc.M710139200","article-title":"Three novel collagen VI chains, alpha4(VI), alpha5(VI), and alpha6(VI)","volume":"283","author":"Fitzgerald","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10658","DOI":"10.1074\/jbc.M709540200","article-title":"Three novel collagen VI chains with high homology to the alpha3 chain","volume":"283","author":"Gara","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/jid.2010.284","article-title":"Expression of the collagen VI alpha5 and alpha6 chains in normal human skin and in skin of patients with collagen VI-related myopathies","volume":"131","author":"Sabatelli","year":"2011","journal-title":"J. Investig. Dermatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"397","DOI":"10.3109\/03008207.2014.959119","article-title":"Distribution and expression of type VI collagen and elastic fibers in human rotator cuff tendon tears","volume":"55","author":"Thakkar","year":"2014","journal-title":"Connect. Tissue Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"131","DOI":"10.3389\/fnagi.2016.00131","article-title":"Tendon extracellular matrix alterations in ullrich congenital muscular dystrophy","volume":"8","author":"Sardone","year":"2016","journal-title":"Front. Aging Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.ejpn.2015.04.002","article-title":"Paternal germline mosaicism in collagen VI related myopathies","volume":"19","author":"Armaroli","year":"2015","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.1080\/15548627.2016.1231279","article-title":"Autophagy activation in COL6 myopathic patients by a low-protein-diet pilot trial","volume":"12","author":"Castagnaro","year":"2016","journal-title":"Autophagy"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1002\/jor.20483","article-title":"Is cultured tendon fibroblast a good model to study tendon healing?","volume":"26","author":"Fu","year":"2008","journal-title":"J. Orthop. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1294\/jes.24.17","article-title":"Tenascin-C expression in equine tendon-derived cells during proliferation and migration","volume":"24","author":"Nemoto","year":"2013","journal-title":"J. Equine Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1083\/jcb.102.3.703","article-title":"Molecular assembly, secretion, and matrix deposition of type VI collagen","volume":"102","author":"Engvall","year":"1986","journal-title":"J. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.matbio.2011.12.003","article-title":"Expression of collagen VI \u03b15 and \u03b16 chains in human muscle and in Duchenne muscular dystrophy-related muscle fibrosis","volume":"31","author":"Sabatelli","year":"2012","journal-title":"Matrix Biol."},{"key":"ref_22","first-page":"171","article-title":"Multifluorescence labeling and colocalization analyses","volume":"285","author":"Riccio","year":"2004","journal-title":"Methods Mol. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4.16.1","DOI":"10.1002\/0471143030.cb0419s52","article-title":"Quantitative colocalization analysis of confocal fluorescence microscopy images","volume":"52","author":"Zinchuk","year":"2011","journal-title":"Curr. Protoc. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1242\/jcs.103.3.857","article-title":"Dynamics of three-dimensional replication patterns during the S-phase, analysed by double labelling of DNA and confocal microscopy","volume":"103","author":"Manders","year":"1992","journal-title":"J. Cell Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.matbio.2016.02.012","article-title":"Collagen VI-NG2 axis in human tendon fibroblasts under conditions mimicking injury response","volume":"55","author":"Sardone","year":"2016","journal-title":"Matrix Biol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Veidal, S.S., Karsdal, M.A., Vassiliadis, E., Nawrocki, A., Larsen, M.R., Nguyen, Q.H., H\u00e4gglund, P., Luo, Y., Zheng, Q., and Vainer, B. (2011). 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.","DOI":"10.1371\/journal.pone.0024753"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.matbio.2010.10.001","article-title":"Dysfunctional tendon collagen fibrillogenesis in collagen VI null mice","volume":"30","author":"Izu","year":"2011","journal-title":"Matrix Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"14320","DOI":"10.1074\/jbc.M112.433078","article-title":"COL6A3 protein deficiency in mice leads to muscle and tendon defects similar to human collagen VI congenital muscular dystrophy","volume":"288","author":"Pan","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1016\/j.bbadis.2014.05.033","article-title":"Defective collagen VI \u03b16 chain expression in the skeletal muscle of patients with collagen VI-related myopathies","volume":"1842","author":"Tagliavini","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_30","first-page":"348","article-title":"Collagen VI disorders: Insights on form and function in the extracellular matrix and beyond","volume":"71\u201372","author":"Bateman","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"281","DOI":"10.32098\/mltj.04.2013.08","article-title":"Ultrastructural changes in muscle cells of patients with collagen VI-related myopathies","volume":"3","author":"Tagliavini","year":"2013","journal-title":"Muscles Ligaments Tendons J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1074\/jbc.M109932200","article-title":"Kinked collagen VI tetramers and reduced microfibril formation as a result of Bethlem myopathy and introduced triple helical glycine mutations","volume":"277","author":"Selan","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.matbio.2009.08.001","article-title":"The alpha 2 chain of collagen type VI sequesters latent proforms of matrix-metalloproteinases and modulates their activation and activity","volume":"28","author":"Freise","year":"2009","journal-title":"Matrix Biol."},{"key":"ref_34","first-page":"130451","article-title":"Intracellular regulation of matrix metalloproteinase-2 activity: New strategies in treatment and protection of heart subjected to oxidative stress","volume":"2013","author":"Sawicki","year":"2013","journal-title":"Scientifica (Cairo)"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s00441-009-0755-4","article-title":"Collagen fibril growth during chicken tendon development: Matrix metalloproteinase-2 and its activation","volume":"336","author":"Jung","year":"2009","journal-title":"Cell Tissue Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/S0945-053X(01)00160-3","article-title":"Collagen VI deficiency affects the organization of fibronectin in the extracellular matrix of cultured fibroblasts","volume":"20","author":"Sabatelli","year":"2001","journal-title":"Matrix Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1002\/ajmg.a.30443","article-title":"Ullrich congenital muscular dystrophy: Connective tissue abnormalities in the skin support overlap with Ehlers-Danlos syndromes","volume":"132A","author":"Kirschner","year":"2005","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10293","DOI":"10.1074\/jbc.M114.549311","article-title":"A mouse model for dominant collagen VI disorders: Heterozygous deletion of Col6a3 Exon 16","volume":"289","author":"Pan","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_39","first-page":"221","article-title":"Abnormality of dermal collagen fibrils in Ehlers Danlos syndrome. Anticipation of the abnormality for the inherited hypermobile disorders","volume":"14","author":"Kobayasi","year":"2004","journal-title":"Eur. J. Dermatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1016\/j.ajpath.2015.01.031","article-title":"Targeted deletion of collagen V in tendons and ligaments results in a classic Ehlers-Danlos syndrome joint phenotype","volume":"185","author":"Sun","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_41","first-page":"115","article-title":"In vivo investigation of tendon responses to mechanical loading","volume":"11","author":"Heinemeier","year":"2011","journal-title":"J. Musculoskelet. Neuronal Interact."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1097\/jes.0b013e3180a030ec","article-title":"Plasticity of the muscle-tendon complex with disuse and aging","volume":"35","author":"Narici","year":"2007","journal-title":"Exerc. Sport Sci. Rev."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/2\/409\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:56:41Z","timestamp":1760173001000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/2\/409"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,11]]},"references-count":42,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["cells9020409"],"URL":"https:\/\/doi.org\/10.3390\/cells9020409","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,11]]}}}