{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T23:33:03Z","timestamp":1793748783879,"version":"4.6.1"},"reference-count":115,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>The phenotypic presentation of monogenetic diseases is determined not only by the nature of the causative mutations but also is influenced by manifold cellular, microenvironmental, and external factors. Here, heritable extracellular matrix diseases, including dystrophic epidermolysis bullosa (DEB), are no exceptions. Dystrophic epidermolysis bullosa is caused by mutations in the<jats:italic>COL7A1<\/jats:italic>gene encoding collagen VII. Deficiency of collagen VII leads to skin and mucosal fragility, which progresses from skin blistering to severe fibrosis and cancer. Clinical and pre-clinical studies suggest that targeting of secondary disease mechanisms or employment of natural disease modifiers can alleviate DEB severity and progression. However, since many of these mechanisms are needed for tissue homeostasis, informed, selective targeting is essential for safe and efficacious treatment. Here, we discuss a selection of key disease modifiers and modifying processes active in DEB, summarize the still scattered knowledge of them, and reflect on ways forward toward their utilization for symptom-relief or enhancement of curative therapies.<\/jats:p>","DOI":"10.3389\/fgene.2021.737272","type":"journal-article","created":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T05:39:33Z","timestamp":1632807573000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":51,"title":["Dystrophic Epidermolysis Bullosa: Secondary Disease Mechanisms and Disease Modifiers"],"prefix":"10.3389","volume":"12","author":[{"given":"Alexander","family":"Nystr\u00f6m","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leena","family":"Bruckner-Tuderman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitra","family":"Kiritsi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,28]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/S0945-053X(98)90100-7","article-title":"Two-hybrid analysis reveals multiple direct interactions for thrombospondin 1","volume":"17","author":"Aho","year":"1998","journal-title":"Matrix Biol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1016\/j.jid.2020.10.024","article-title":"Diversity of mechanisms underlying latent TGF-\u03b2 activation in recessive dystrophic epidermolysis bullosa","volume":"141","author":"Akasaka","year":"2021","journal-title":"J. Invest. Dermatol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"262","DOI":"10.2340\/00015555-1053","article-title":"Identical glycine substitution mutations in type VII collagen may underlie both dominant and recessive forms of dystrophic epidermolysis bullosa","volume":"91","author":"Almaani","year":"2011","journal-title":"Acta Derm. Venereol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"6","DOI":"10.2340\/00015555-0605","article-title":"New glycine substitution mutations in type VII collagen underlying epidermolysis bullosa pruriginosa but the phenotype is not explained by a common polymorphism in the matrix metalloproteinase-1 gene promoter","volume":"89","author":"Almaani","year":"2009","journal-title":"Acta Derm. Venereol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"e1528","DOI":"10.1097\/MD.0000000000001528","article-title":"Proinflammatory cytokines and Antiskin autoantibodies in patients With inherited epidermolysis bullosa","volume":"94","author":"Annicchiarico","year":"2015","journal-title":"Medicine"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1007\/BF03401916","article-title":"Basic fibroblast growth factor: a missing link between collagen VII, increased collagenase, and squamous cell carcinoma in recessive dystrophic epidermolysis bullosa","volume":"4","author":"Arbiser","year":"1998","journal-title":"Mol. Med."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1016\/j.jid.2019.01.011","article-title":"Thrombospondin-1 is a major activator of TGF-\u03b2 signaling in recessive dystrophic epidermolysis bullosa fibroblasts","volume":"139","author":"Atanasova","year":"2019","journal-title":"J. Invest. Dermatol."},{"key":"ref8","doi-asserted-by":"crossref","DOI":"10.1111\/ced.14592","article-title":"Evidence for cutaneous dysbiosis in dystrophic epidermolysis bullosa","volume-title":"Clin. Exp. Dermatol.","author":"Bar","year":"2021"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/s41572-020-0210-0","article-title":"Epidermolysis bullosa","volume":"6","author":"Bardhan","year":"2020","journal-title":"Nat. Rev. Dis. Primers."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1056\/NEJM198010023031402","article-title":"Phenytoin therapy of recessive dystrophic epidermolysis bullosa. Clinical trial and proposed mechanism of action on collagenase","volume":"303","author":"Bauer","year":"1980","journal-title":"N. Engl. J. Med."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.1084\/jem.148.5.1378","article-title":"Recessive dystrophic epidermolysis bullosa. Evidence for increased collagenase as a genetic characteristic in cell culture","volume":"148","author":"Bauer","year":"1978","journal-title":"J. Exp. Med."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"2280","DOI":"10.1016\/j.jid.2020.02.040","article-title":"Proteomic profiling of fibroblasts isolated from chronic wounds identifies disease-relevant signaling pathways","volume":"140","author":"Berberich","year":"2020","journal-title":"J. Invest. Dermatol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1046\/j.1523-1747.2003.12325.x","article-title":"Skin expression of metalloproteinases and tissue inhibitor of metalloproteinases in sibling patients with recessive dystrophic epidermolysis and intrafamilial phenotypic variation","volume":"121","author":"Bodemer","year":"2003","journal-title":"J. Invest. Dermatol."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1111\/ddg.12839","article-title":"Pseudosyndactyly - an inflammatory and fibrotic wound healing disorder in recessive dystrophic epidermolysis bullosa","volume":"13","author":"Breitenbach","year":"","journal-title":"J. Dtsch. Dermatol. Ges."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"389","DOI":"10.18632\/aging.100755","article-title":"Transcriptome and ultrastructural changes in dystrophic epidermolysis bullosa resemble skin aging","volume":"7","author":"Breitenbach","year":"","journal-title":"Aging"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1016\/j.bbrc.2006.03.034","article-title":"High-affinity binding of the NC1 domain of collagen VII to laminin 5 and collagen IV","volume":"343","author":"Brittingham","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1177\/0003489417729833","article-title":"Successful placement of a BAHA implant in a patient With epidermolysis bullosa: a case report and review of the literature","volume":"126","author":"Brown","year":"2017","journal-title":"Ann. Otol. Rhinol. Laryngol."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1083\/jcb.131.2.551","article-title":"Immunohistochemical and mutation analyses demonstrate that procollagen VII is processed to collagen VII through removal of the NC-2 domain","volume":"131","author":"Bruckner-Tuderman","year":"1995","journal-title":"J. Cell Biol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1056\/NEJM199207163270305","article-title":"Lack of efficacy of phenytoin in recessive dystrophic epidermolysis bullosa. Epidermolysis bullosa study group","volume":"327","author":"Caldwell-Brown","year":"1992","journal-title":"N. Engl. J. Med."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1111\/bjd.17698","article-title":"Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses","volume":"181","author":"Chac\u00f3n-Solano","year":"2019","journal-title":"Br. J. Dermatol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"21649","DOI":"10.1074\/jbc.M100180200","article-title":"The carboxyl terminus of type VII collagen mediates antiparallel dimer formation and constitutes a new antigenic epitope for epidermolysis bullosa acquisita autoantibodies","volume":"276","author":"Chen","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1046\/j.1523-1747.1999.00491.x","article-title":"NC1 domain of type VII collagen binds to the beta3 chain of laminin 5 via a unique subdomain within the fibronectin-like repeats","volume":"112","author":"Chen","year":"1999","journal-title":"J. Invest. Dermatol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"14516","DOI":"10.1074\/jbc.272.23.14516","article-title":"Interactions of the amino-terminal noncollagenous (NC1) domain of type VII collagen with extracellular matrix components. A potential role in epidermal-dermal adherence in human skin","volume":"272","author":"Chen","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"eaas9668","DOI":"10.1126\/scitranslmed.aas9668","article-title":"APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa","volume":"10","author":"Cho","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1007\/BF00917477","article-title":"Patients with severe forms of inherited epidermolysis bullosa exhibit decreased lymphokine and monokine production","volume":"10","author":"Chopra","year":"1990","journal-title":"J. Clin. Immunol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1001\/archderm.1992.01680120073006","article-title":"Peripheral blood mononuclear cell subsets in patients with severe inherited forms of epidermolysis bullosa","volume":"128","author":"Chopra","year":"1992","journal-title":"Arch. Dermatol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.det.2009.10.011","article-title":"Type VII collagen: the anchoring fibril protein at fault in dystrophic epidermolysis bullosa","volume":"28","author":"Chung","year":"2010","journal-title":"Dermatol. Clin."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.matbio.2018.12.001","article-title":"Decorin counteracts disease progression in mice with recessive dystrophic epidermolysis bullosa","volume":"81","author":"Cianfarani","year":"2019","journal-title":"Matrix Biol."},{"key":"ref29","unstructured":"2020"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"5707","DOI":"10.3390\/ijms20225707","article-title":"Epidermolysis bullosa-associated squamous cell carcinoma: From pathogenesis to therapeutic perspectives","volume":"20","author":"Condorelli","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1111\/j.1600-0625.2008.00723.x","article-title":"Mutation analysis and characterization of COL7A1 mutations in dystrophic epidermolysis bullosa","volume":"17","author":"Dang","year":"2008","journal-title":"Exp. Dermatol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1238","DOI":"10.1111\/bjd.17858","article-title":"Bone marrow transplant with post-transplant cyclophosphamide for recessive dystrophic epidermolysis bullosa expands the related donor pool and permits tolerance of nonhaematopoietic cellular grafts","volume":"181","author":"Ebens","year":"2019","journal-title":"Br. J. Dermatol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1038\/jid.1969.77","article-title":"Human skin collagenase: relationship to the pathogenesis of epidermolysis bullosa dystrophica","volume":"52","author":"Eisen","year":"1969","journal-title":"J. Invest. Dermatol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.3390\/ijms17101625","article-title":"Autoimmunity and cytokine imbalance in inherited epidermolysis bullosa","volume":"17","author":"Esposito","year":"2016","journal-title":"Int. J. Mol. Sci."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"984","DOI":"10.3390\/cells8090984","article-title":"The rebirth of matrix metalloproteinase inhibitors: moving Beyond the dogma","volume":"8","author":"Fields","year":"2019","journal-title":"Cell"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.det.2009.10.021","article-title":"Ophthalmic involvement in inherited epidermolysis bullosa","volume":"28","author":"Figueira","year":"2010","journal-title":"Dermatol. Clin."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1111\/j.1365-2133.2008.08697.x","article-title":"The risk of cardiomyopathy in inherited epidermolysis bullosa","volume":"159","author":"Fine","year":"2008","journal-title":"Br. J. Dermatol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.jaad.2008.09.035","article-title":"Epidermolysis bullosa and the risk of life-threatening cancers: the national EB registry experience, 1986-2006","volume":"60","author":"Fine","year":"2009","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.matbio.2017.11.004","article-title":"Identification of tissue damage, extracellular matrix remodeling and bacterial challenge as common mechanisms associated with high-risk cutaneous squamous cell carcinomas","volume":"66","author":"F\u00f6ll","year":"2017","journal-title":"Matrix Biol."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1669","DOI":"10.1172\/JCI34292","article-title":"A hypomorphic mouse model of dystrophic epidermolysis bullosa reveals mechanisms of disease and response to fibroblast therapy","volume":"118","author":"Fritsch","year":"2008","journal-title":"J. Clin. Invest."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"2492","DOI":"10.1016\/j.jid.2018.04.026","article-title":"Reduced microbial diversity is a feature of recessive dystrophic epidermolysis bullosa-involved skin and wounds","volume":"138","author":"Fuentes","year":"2018","journal-title":"J. Invest. Dermatol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.matbio.2017.01.002","article-title":"Stromal microenvironment in type VII collagen-deficient skin: the ground for squamous cell carcinoma development","volume":"63","author":"Guerra","year":"2017","journal-title":"Matrix Biol."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1126\/science.1124287","article-title":"Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome","volume":"312","author":"Habashi","year":"2006","journal-title":"Science"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1111\/bjd.18921","article-title":"Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility","volume":"183","author":"Has","year":"2020","journal-title":"Br. J. Dermatol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.matbio.2018.04.001","article-title":"Epidermolysis bullosa: molecular pathology of connective tissue components in the cutaneous basement membrane zone","volume":"72","author":"Has","year":"2018","journal-title":"Matrix Biol."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.matbio.2015.05.006","article-title":"The extracellular matrix and transforming growth factor-\u03b21: tale of a strained relationship","volume":"47","author":"Hinz","year":"2015","journal-title":"Matrix Biol."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"5932","DOI":"10.1038\/ncomms6932","article-title":"Innate sensing of microbial products promotes wound-induced skin cancer","volume":"6","author":"Hoste","year":"2015","journal-title":"Nat. Commun."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1086\/515495","article-title":"Characterization of 18 new mutations in COL7A1 in recessive dystrophic epidermolysis bullosa provides evidence for distinct molecular mechanisms underlying defective anchoring fibril formation","volume":"61","author":"Hovnanian","year":"1997","journal-title":"Am. J. Hum. Genet."},{"key":"ref50","doi-asserted-by":"publisher","first-page":"21671","DOI":"10.1073\/pnas.1016233107","article-title":"Target-seeking antifibrotic compound enhances wound healing and suppresses scar formation in mice","volume":"107","author":"J\u00e4rvinen","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1111\/j.1365-2133.2009.09333.x","article-title":"Forty-two novel COL7A1 mutations and the role of a frequent single nucleotide polymorphism in the MMP1 promoter in modulation of disease severity in a large European dystrophic epidermolysis bullosa cohort","volume":"161","author":"Kern","year":"2009","journal-title":"Br. J. Dermatol."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"a022293","DOI":"10.1101\/cshperspect.a022293","article-title":"TGF-\u03b21 signaling and tissue fibrosis","volume":"10","author":"Kim","year":"2018","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1007\/s40257-015-0119-7","article-title":"Epidermolysis bullosa pruriginosa: a systematic review exploring genotype-phenotype correlation","volume":"16","author":"Kim","year":"2015","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref32","first-page":"7","article-title":"Acta Dermato-Venereologica","author":"Kiritsi","year":"2020"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.mad.2017.11.004","article-title":"The role of TGF\u03b2 in wound healing pathologies","volume":"172","author":"Kiritsi","year":"2018","journal-title":"Mech. Ageing Dev."},{"key":"ref55","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1155\/2011\/153108","article-title":"TGF\u03b2-signaling in squamous cell carcinoma occurring in recessive dystrophic epidermolysis bullosa","volume":"34","author":"Knaup","year":"2011","journal-title":"Anal. Cell. Pathol."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/scd.12511","article-title":"Clinical practice guidelines: Oral health care for children and adults living with epidermolysis bullosa","volume":"40","author":"Kr\u00e4mer","year":"2020","journal-title":"Spec. Care Dentist."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"100065","DOI":"10.1016\/j.mbplus.2021.100065","article-title":"Distinct contributions of meprins to skin regeneration after injury \u2013 meprin \u03b1 a physiological processer of pro-collagen VII","volume":"11","author":"Kruppa","year":"2021","journal-title":"Matrix Biology Plus"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"1368","DOI":"10.1038\/mt.2015.58","article-title":"High local concentrations of intradermal MSCs restore skin integrity and facilitate wound healing in dystrophic epidermolysis bullosa","volume":"23","author":"K\u00fchl","year":"2015","journal-title":"Mol. Ther."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"2381","DOI":"10.1038\/jid.2014.185","article-title":"Loss of collagen VII is associated with reduced transglutaminase 2 abundance and activity","volume":"134","author":"K\u00fcttner","year":"2014","journal-title":"J. Invest. Dermatol."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1038\/msb.2013.17","article-title":"Global remodelling of cellular microenvironment due to loss of collagen VII","volume":"9","author":"K\u00fcttner","year":"2013","journal-title":"Mol. Syst. Biol."},{"key":"ref61","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1111\/1523-1747.ep12539946","article-title":"Collagenase and connective tissue metabolism in epidermolysis bullosa","volume":"58","author":"Lazarus","year":"1972","journal-title":"J. Invest. Dermatol."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1111\/pde.14444","article-title":"Characterization of wound microbes in epidermolysis bullosa: results from the epidermolysis bullosa clinical characterization and outcomes database","volume":"38","author":"Levin","year":"2021","journal-title":"Pediatr. Dermatol."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"1839","DOI":"10.1002\/stem.2907","article-title":"Cord blood-derived stem cells suppress fibrosis and May prevent malignant progression in recessive dystrophic epidermolysis bullosa","volume":"36","author":"Liao","year":"2018","journal-title":"Stem Cells"},{"key":"ref64","doi-asserted-by":"publisher","first-page":"1221","DOI":"10.1016\/j.jid.2018.11.036","article-title":"Gene therapy for epidermolysis bullosa","volume":"139","author":"Marinkovich","year":"2019","journal-title":"J. Invest. Dermatol."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"djv293","DOI":"10.1093\/jnci\/djv293","article-title":"Suppression of TGF\u03b2 and angiogenesis by type VII collagen in cutaneous SCC","volume":"108","author":"Martins","year":"2016","journal-title":"J. Natl. Cancer Inst."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"576558","DOI":"10.3389\/fmed.2020.576558","article-title":"Beneficial effect of systemic allogeneic adipose derived mesenchymal cells on the clinical, inflammatory and immunologic status of a patient With recessive dystrophic epidermolysis bullosa: a case report","volume":"7","author":"Maseda","year":"2020","journal-title":"Front. Med."},{"key":"ref67","doi-asserted-by":"publisher","first-page":"940","DOI":"10.1158\/0008-5472.CAN-15-1348","article-title":"Injury-driven stiffening of the dermis expedites skin carcinoma progression","volume":"76","author":"Mittapalli","year":"2016","journal-title":"Cancer Res."},{"key":"ref68","doi-asserted-by":"publisher","first-page":"24188","DOI":"10.1074\/jbc.M501486200","article-title":"Substrate-specific modulation of a multisubstrate proteinase. C-terminal processing of fibrillar procollagens is the only BMP-1-dependent activity to be enhanced by PCPE-1","volume":"280","author":"Moali","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref69","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s13023-016-0489-9","article-title":"Inherited epidermolysis bullosa and squamous cell carcinoma: a systematic review of 117 cases","volume":"11","author":"Montaudi\u00e9","year":"2016","journal-title":"Orphanet J. Rare Dis."},{"key":"ref70","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.ajpath.2012.04.029","article-title":"Decorin: a guardian from the matrix","volume":"181","author":"Neill","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref71","doi-asserted-by":"publisher","first-page":"3522","DOI":"10.1158\/0008-5472.CAN-11-2996","article-title":"Fibroblast-derived dermal matrix drives development of aggressive cutaneous squamous cell carcinoma in patients with recessive dystrophic epidermolysis bullosa","volume":"72","author":"Ng","year":"2012","journal-title":"Cancer Res."},{"key":"ref72","doi-asserted-by":"publisher","first-page":"E705","DOI":"10.1073\/pnas.1709111115","article-title":"Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa","volume":"115","author":"Nystr\u00f6m","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref73","doi-asserted-by":"publisher","first-page":"2035","DOI":"10.1038\/mt.2016.199","article-title":"Gene therapy for epidermolysis bullosa: sticky business","volume":"24","author":"Nystr\u00f6m","year":"2016","journal-title":"Mol. Ther."},{"key":"ref74","doi-asserted-by":"publisher","first-page":"e64243","DOI":"10.1371\/journal.pone.0064243","article-title":"Rat model for dominant dystrophic epidermolysis bullosa: glycine substitution reduces collagen VII stability and shows gene-dosage effect","volume":"8","author":"Nystr\u00f6m","year":"","journal-title":"PLoS One"},{"key":"ref75","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.15252\/emmm.201505061","article-title":"Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms","volume":"7","author":"Nystr\u00f6m","year":"2015","journal-title":"EMBO Mol. Med."},{"key":"ref76","doi-asserted-by":"publisher","first-page":"3498","DOI":"10.1172\/JCI68127","article-title":"Collagen VII plays a dual role in wound healing","volume":"123","author":"Nystr\u00f6m","year":"","journal-title":"J. Clin. Invest."},{"key":"ref77","doi-asserted-by":"publisher","first-page":"3907","DOI":"10.1093\/hmg\/ddu102","article-title":"Monozygotic twins discordant for recessive dystrophic epidermolysis bullosa phenotype highlight the role of TGF-\u03b2 signalling in modifying disease severity","volume":"23","author":"Odorisio","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref78","doi-asserted-by":"publisher","first-page":"1833","DOI":"10.1016\/j.ymthe.2020.05.017","article-title":"Exposed CendR domain in homing peptide yields skin-targeted therapeutic in epidermolysis bullosa","volume":"28","author":"Pemmari","year":"2020","journal-title":"Mol. Ther."},{"key":"ref79","doi-asserted-by":"publisher","first-page":"2319","DOI":"10.1038\/jid.2015.158","article-title":"Potential of systemic allogeneic mesenchymal stromal cell therapy for children with recessive dystrophic epidermolysis bullosa","volume":"135","author":"Petrof","year":"2015","journal-title":"J. Invest. Dermatol."},{"key":"ref80","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1016\/j.immuni.2013.01.015","article-title":"Cochlin produced by follicular dendritic cells promotes antibacterial innate immunity","volume":"38","author":"Py","year":"2013","journal-title":"Immunity"},{"key":"ref81","doi-asserted-by":"publisher","first-page":"1174","DOI":"10.1172\/JCI118901","article-title":"Cross-linking of the dermo-epidermal junction of skin regenerating from keratinocyte autografts. Anchoring fibrils are a target for tissue transglutaminase","volume":"98","author":"Raghunath","year":"1996","journal-title":"J. Clin. Invest."},{"key":"ref82","doi-asserted-by":"crossref","DOI":"10.1111\/exd.14349","article-title":"Complement factor I upregulates expression of matrix metalloproteinase-13 and -2 and promotes invasion of cutaneous squamous carcinoma cells","volume-title":"Exp. Dermatol.","author":"Rahmati Nezhad","year":"2021"},{"key":"ref83","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1089\/wound.2013.0466","article-title":"The role of TGF\u03b2 signaling in wound epithelialization","volume":"3","author":"Ramirez","year":"2014","journal-title":"Adv. Wound Care"},{"key":"ref84","doi-asserted-by":"publisher","first-page":"26372","DOI":"10.1074\/jbc.M203247200","article-title":"Proteinases of the bone morphogenetic protein-1 family convert procollagen VII to mature anchoring fibril collagen","volume":"277","author":"Rattenholl","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref85","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1111\/bjd.18475","article-title":"Natural history of growth and anaemia in children with epidermolysis bullosa: a retrospective cohort study","volume":"182","author":"Reimer","year":"2020","journal-title":"Br. J. Dermatol."},{"key":"ref86","doi-asserted-by":"publisher","first-page":"28204","DOI":"10.1074\/jbc.M109.038190","article-title":"Reduction of lysyl hydroxylase 3 causes deleterious changes in the deposition and organization of extracellular matrix","volume":"284","author":"Risteli","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref87","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/S0006-291X(05)81118-0","article-title":"Transforming growth factor-beta up-regulates type VII collagen gene expression in normal and transformed epidermal keratinocytes in culture","volume":"180","author":"Ryyn\u00e4nen","year":"1991","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref88","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1172\/JCI45817","article-title":"Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors","volume":"122","author":"Salmon","year":"2012","journal-title":"J. Clin. Invest."},{"key":"ref89","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1016\/j.ajhg.2008.09.004","article-title":"A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene","volume":"83","author":"Salo","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref90","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1002\/jcp.20596","article-title":"Lysyl hydroxylase 3 (LH3) modifies proteins in the extracellular space, a novel mechanism for matrix remodeling","volume":"207","author":"Salo","year":"2006","journal-title":"J. Cell. Physiol."},{"key":"ref91","doi-asserted-by":"publisher","first-page":"a022236","DOI":"10.1101\/cshperspect.a022236","article-title":"Regulation of the immune response by TGF-\u03b2: From conception to autoimmunity and infection","volume":"9","author":"Sanjabi","year":"2017","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref92","doi-asserted-by":"publisher","first-page":"dmm048082","DOI":"10.1242\/dmm.048082","article-title":"Mouse models for dominant dystrophic epidermolysis bullosa (DDEB) carrying common human point mutations recapitulate the human disease","volume":"14","author":"Smith","year":"2021","journal-title":"Dis. Model. Mech."},{"key":"ref93","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1111\/pde.14576","article-title":"Clinical characteristics associated with increased wound size in patients with recessive dystrophic epidermolysis bullosa","volume":"38","author":"Solis","year":"2021","journal-title":"Pediatr. Dermatol."},{"key":"ref94","doi-asserted-by":"publisher","first-page":"1242","DOI":"10.1177\/0963689719857657","article-title":"Collagen VII expression is required in Both keratinocytes and fibroblasts for anchoring fibril formation in bilayer engineered skin substitutes","volume":"28","author":"Supp","year":"2019","journal-title":"Cell Transplant."},{"key":"ref95","first-page":"340","article-title":"IL-6\/IL-10 ratio as A prognostic and predictive marker of the severity of inherited epidermolysis bullosa","volume":"14","author":"Tampoia","year":"2017","journal-title":"Iran. J. Immunol."},{"key":"ref96","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1186\/1750-1172-8-132","article-title":"Prevalence of specific anti-skin autoantibodies in a cohort of patients with inherited epidermolysis bullosa","volume":"8","author":"Tampoia","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref97","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1074\/mcp.RA117.000437","article-title":"Combinatorial omics analysis reveals perturbed lysosomal homeostasis in collagen VII-deficient keratinocytes. Mol","volume":"17","author":"Thriene","year":"2018","journal-title":"Cell Proteomics"},{"key":"ref98","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1002\/humu.20647","article-title":"A frequent functional SNP in the MMP1 promoter is associated with higher disease severity in recessive dystrophic epidermolysis bullosa","volume":"29","author":"Titeux","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref99","doi-asserted-by":"publisher","first-page":"1283","DOI":"10.1038\/mt.2015.84","article-title":"From mesoderm to Mesodermatology: bone marrow mesenchymal cells heal skin wounds","volume":"23","author":"Tolarova","year":"2015","journal-title":"Mol. Ther."},{"key":"ref100","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1111\/bjd.17943","article-title":"Revertant mosaic fibroblasts in recessive dystrophic epidermolysis bullosa","volume":"181","author":"Twaroski","year":"2019","journal-title":"Br. J. Dermatol."},{"key":"ref101","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1001\/archderm.1989.01670180069008","article-title":"Natural killer cell activity is reduced in patients with severe forms of inherited epidermolysis bullosa","volume":"125","author":"Tyring","year":"1989","journal-title":"Arch. Dermatol."},{"key":"ref102","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.matbio.2018.11.006","article-title":"Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency","volume":"81","author":"Vahidnezhad","year":"2019","journal-title":"Matrix Biol."},{"key":"ref103","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1172\/JCI109842","article-title":"Enhanced biosynthesis of human skin collagenase in fibroblast cultures from recessive dystrophic epidermolysis bullosa","volume":"66","author":"Valle","year":"1980","journal-title":"J. Clin. Invest."},{"key":"ref104","doi-asserted-by":"publisher","first-page":"160","DOI":"10.1136\/jmg.2010.082230","article-title":"The inversa type of recessive dystrophic epidermolysis bullosa is caused by specific arginine and glycine substitutions in type VII collagen","volume":"48","author":"van den Akker","year":"2011","journal-title":"J. Med. Genet."},{"key":"ref105","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.jdermsci.2009.06.015","article-title":"Long-term follow-up of patients with recessive dystrophic epidermolysis bullosa in the Netherlands: expansion of the mutation database and unusual phenotype-genotype correlations","volume":"56","author":"van den Akker","year":"2009","journal-title":"J. Dermatol. Sci."},{"key":"ref106","doi-asserted-by":"publisher","first-page":"24506","DOI":"10.1074\/jbc.M802415200","article-title":"Supramolecular interactions in the dermo-epidermal junction zone: anchoring fibril-collagen VII tightly binds to banded collagen fibrils","volume":"283","author":"Villone","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref107","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1056\/NEJMoa0910501","article-title":"Bone marrow transplantation for recessive dystrophic epidermolysis bullosa","volume":"363","author":"Wagner","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref108","doi-asserted-by":"publisher","first-page":"E4168","DOI":"10.1073\/pnas.1705129114","article-title":"Atypical interactions of integrin \u03b1V\u03b28 with pro-TGF-\u03b21","volume":"114","author":"Wang","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref109","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1091\/mbc.E11-12-1018","article-title":"GARP regulates the bioavailability and activation of TGF\u03b2","volume":"23","author":"Wang","year":"2012","journal-title":"Mol. Biol. Cell"},{"key":"ref110","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1038\/mt.2013.87","article-title":"Topical application of recombinant type VII collagen incorporates Into the dermal-epidermal junction and promotes wound closure","volume":"21","author":"Wang","year":"2013","journal-title":"Mol. Ther."},{"key":"ref111","doi-asserted-by":"publisher","first-page":"e0137639","DOI":"10.1371\/journal.pone.0137639","article-title":"Lysyl hydroxylase 3 localizes to epidermal basement membrane and is reduced in patients with recessive dystrophic epidermolysis bullosa","volume":"10","author":"Watt","year":"2015","journal-title":"PLoS One"},{"key":"ref112","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1111\/1523-1747.ep13071274","article-title":"Collagenase expression in skin fibroblasts from families with recessive dystrophic epidermolysis bullosa","volume":"92","author":"Winberg","year":"1989","journal-title":"J. Invest. Dermatol."},{"key":"ref113","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1158\/1535-7163.MCT-17-0646","article-title":"Matrix metalloproteinase inhibitors in cancer therapy: turning past failures Into future successes","volume":"17","author":"Winer","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref114","doi-asserted-by":"publisher","first-page":"1138","DOI":"10.1038\/jid.2013.475","article-title":"De novo anti-type VII collagen antibodies in patients with recessive dystrophic epidermolysis bullosa","volume":"134","author":"Woodley","year":"2014","journal-title":"J. Invest. Dermatol."},{"key":"ref115","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1038\/346281a0","article-title":"Negative regulation of transforming growth factor-beta by the proteoglycan decorin","volume":"346","author":"Yamaguchi","year":"1990","journal-title":"Nature"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.737272\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,10]],"date-time":"2023-01-10T11:25:15Z","timestamp":1673349915000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2021.737272\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,28]]},"references-count":115,"alternative-id":["10.3389\/fgene.2021.737272"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2021.737272","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,28]]},"article-number":"737272"}}