{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T14:14:21Z","timestamp":1790172861370,"version":"4.1.0"},"reference-count":58,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,4,4]],"date-time":"2020-04-04T00:00:00Z","timestamp":1585958400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100005614","name":"Biogen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005614","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001845","name":"Scleroderma Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001845","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008590","name":"Dr. Ralph and Marian Falk Medical Research Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008590","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"published-print":{"date-parts":[[2020,5]]},"abstract":"\n Objective<\/jats:title>\n \n Systemic sclerosis (\n SS<\/jats:styled-content>\n c) is a clinically heterogeneous disease characterized by increased collagen accumulation and skin stiffness. Our previous work has demonstrated that transforming growth factor \u03b2 (\n TGF<\/jats:styled-content>\n \u03b2) induces extracellular matrix (\n ECM<\/jats:styled-content>\n ) modifications through lysyl oxidase\n \u2013<\/jats:bold>\n like 4 (\n LOXL<\/jats:styled-content>\n \u20104), a collagen crosslinking enzyme, in bioengineered human skin equivalents (\n HSE<\/jats:styled-content>\n s) and self\u2010assembled stromal tissues (\n SAS<\/jats:styled-content>\n ). We undertook this study to investigate cutaneous fibrosis and the role of\n LOXL<\/jats:styled-content>\n \u20104 in\n SS<\/jats:styled-content>\n c pathogenesis using\n HSE<\/jats:styled-content>\n s and\n SAS<\/jats:styled-content>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n SS<\/jats:styled-content>\n c\u2010derived dermal fibroblasts (\n SS<\/jats:styled-content>\n c\n DF<\/jats:styled-content>\n s; n = 8) and normal dermal fibroblasts (\n NDF<\/jats:styled-content>\n s; n = 6) were incorporated into\n HSE<\/jats:styled-content>\n s and\n SAS<\/jats:styled-content>\n . These 3\u2010dimensional skin\u2010like microenvironments were used to study the effects of dysregulated\n LOXL<\/jats:styled-content>\n \u20104 on\n ECM<\/jats:styled-content>\n remodeling, fibroblast activation, and response to\n TGF<\/jats:styled-content>\n \u03b2 stimulation.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n SS<\/jats:styled-content>\n c\n DF<\/jats:styled-content>\n \u2010containing\n SAS<\/jats:styled-content>\n showed increased stromal thickness, collagen deposition, and interleukin\u20106 secretion compared to\n NDF<\/jats:styled-content>\n \u2010containing\n SAS<\/jats:styled-content>\n (\n P<\/jats:italic>\n < 0.05). In\n HSE<\/jats:styled-content>\n ,\n SS<\/jats:styled-content>\n c\n DF<\/jats:styled-content>\n s altered collagen as seen by a more mature and aligned fibrillar structure (\n P<\/jats:italic>\n < 0.05). With\n SS<\/jats:styled-content>\n c\n DF<\/jats:styled-content>\n s, enhanced stromal rigidity with increased collagen crosslinking (\n P<\/jats:italic>\n < 0.05), up\u2010regulation of\n \n LOXL4<\/jats:styled-content>\n <\/jats:italic>\n expression (\n P<\/jats:italic>\n < 0.01), and innate immune signaling genes were observed in both tissue models. Conversely, knockdown of\n \n LOXL<\/jats:styled-content>\n 4\n <\/jats:italic>\n suppressed rigidity, contraction, and \u03b1\u2010smooth muscle actin expression in\n SS<\/jats:styled-content>\n c\n DF<\/jats:styled-content>\n s in\n HSE<\/jats:styled-content>\n , and\n TGF<\/jats:styled-content>\n \u03b2\u2010induced\n ECM<\/jats:styled-content>\n aggregation and collagen crosslinking in\n SAS<\/jats:styled-content>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n A limitation to the development of effective therapeutics in\n SS<\/jats:styled-content>\n c is the lack of in vitro human model systems that replicate human skin. Our findings demonstrate that\n SAS<\/jats:styled-content>\n and\n HSE<\/jats:styled-content>\n can serve as complementary in vitro skin\u2010like models for investigation of the mechanisms and mediators that drive fibrosis in\n SS<\/jats:styled-content>\n c and implicate a pivotal role for\n LOXL<\/jats:styled-content>\n \u20104 in\n SS<\/jats:styled-content>\n c pathogenesis.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.41163","type":"journal-article","created":{"date-parts":[[2019,11,9]],"date-time":"2019-11-09T04:24:07Z","timestamp":1573273447000},"page":"791-801","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Systemic Sclerosis Dermal Fibroblasts Induce Cutaneous Fibrosis Through Lysyl Oxidase\u2013like 4: New Evidence From Three\u2010Dimensional Skin\u2010like Tissues"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1675-8575","authenticated-orcid":false,"given":"Mengqi","family":"Huang","sequence":"first","affiliation":[{"name":"Tufts University School of Dental Medicine and Boston University School of Medicine, Boston, Massachusetts, and Geisel School of Medicine at Dartmouth Hanover New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoshuai","family":"Cai","sequence":"additional","affiliation":[{"name":"Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, and University of South Carolina Arnold School of Public Health Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren M.","family":"Baugh","sequence":"additional","affiliation":[{"name":"Tufts University Medford Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyi","family":"Liu","sequence":"additional","affiliation":[{"name":"Tufts University, Medford, Massachusetts, and Zhejiang University College of Optical Science and Engineering Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avi","family":"Smith","sequence":"additional","affiliation":[{"name":"Tufts University School of Dental Medicine Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Watson","sequence":"additional","affiliation":[{"name":"Tufts University Medford Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dillon","family":"Popovich","sequence":"additional","affiliation":[{"name":"Geisel School of Medicine at Dartmouth Lebanon New Hampshire"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tufts University School of Dental Medicine Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukasz 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