{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T02:47:49Z","timestamp":1787971669797,"version":"build-2784847793"},"reference-count":51,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,2,5]],"date-time":"2022-02-05T00:00:00Z","timestamp":1644019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Urgo Laboratories (France)","award":["1116\/2010"],"award-info":[{"award-number":["1116\/2010"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Most chronic wounds are characterized by varying degrees of hypoxia and low partial pressures of O2 that may favor the development of the wound and\/or delay healing. However, most studies regarding extracellular matrix remodeling in wound healing are conducted under normoxic conditions. Here, we investigated the consequences of hypoxia on elastic network formation, both in a mouse model of pressure-induced hypoxic ulcer and in human primary fibroblasts cultured under hypoxic conditions. In vitro, hypoxia inhibited elastic fiber synthesis with a reduction in fibrillin-2 expression at the mRNA and protein levels. Lysyl oxidase maturation was reduced, concomitant with lower enzymatic activity. Fibrillin-2 and lysyl oxidase could interact directly, whereas the downregulation of fibrillin-2 was associated with deficient lysyl oxidase maturation. Elastic fibers were not synthesized in the hypoxic inflammatory tissues resulting from in vivo pressure-induced ulcer. Tropoelastin and fibrillin-2 were expressed sparsely in hypoxic tissues stained with carbonic anhydrase IX. Different hypoxic conditions in culture resulted in the arrest of elastic fiber synthesis. The present study demonstrated the involvement of FBN2 in regulating elastin deposition in adult skin models and described the specific impact of hypoxia on the elastin network without consequences on collagen and fibronectin networks.<\/jats:p>","DOI":"10.3390\/ijms23031824","type":"journal-article","created":{"date-parts":[[2022,2,6]],"date-time":"2022-02-06T20:36:47Z","timestamp":1644179807000},"page":"1824","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["FBN2 Silencing Recapitulates Hypoxic Conditions and Induces Elastic Fiber Impairment in Human Dermal Fibroblasts"],"prefix":"10.3390","volume":"23","author":[{"given":"J\u00e9r\u00e9my","family":"Boizot","sequence":"first","affiliation":[{"name":"CNRS UMR 5305, LBTI, 7 Passage du Vercors, CEDEX 7, 69367 Lyon, France"},{"name":"University of Lyon 1, UFR Biosciences, 7 Passage du Vercors, CEDEX 7, 69367 Lyon, France"},{"name":"Urgo Research Innovation and Development, 42 Rue de Longvic, 21300 Chen\u00f4ve, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9laine","family":"Minville-Walz","sequence":"additional","affiliation":[{"name":"Urgo Research Innovation and Development, 42 Rue de Longvic, 21300 Chen\u00f4ve, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dieter Peter","family":"Reinhardt","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Faculty of Medicine, McGill University, Montreal, QC H3A 0C7, Canada"},{"name":"Faculty of Dentistry, McGill University, Montreal, QC H3A 0C7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marielle","family":"Bouschbacher","sequence":"additional","affiliation":[{"name":"Urgo Research Innovation and Development, 42 Rue de Longvic, 21300 Chen\u00f4ve, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"Sommer","sequence":"additional","affiliation":[{"name":"CNRS UMR 5305, LBTI, 7 Passage du Vercors, CEDEX 7, 69367 Lyon, France"},{"name":"University of Lyon 1, UFR Biosciences, 7 Passage du Vercors, CEDEX 7, 69367 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Sigaudo-Roussel","sequence":"additional","affiliation":[{"name":"CNRS UMR 5305, LBTI, 7 Passage du Vercors, CEDEX 7, 69367 Lyon, France"},{"name":"University of Lyon 1, UFR Biosciences, 7 Passage du Vercors, CEDEX 7, 69367 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6315-2616","authenticated-orcid":false,"given":"Romain","family":"Debret","sequence":"additional","affiliation":[{"name":"CNRS UMR 5305, LBTI, 7 Passage du Vercors, CEDEX 7, 69367 Lyon, France"},{"name":"University of Lyon 1, UFR Biosciences, 7 Passage du Vercors, CEDEX 7, 69367 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1038\/sj.cdd.4401632","article-title":"Cellular senescence mechanisms in chronic wound healing","volume":"12","author":"Telgenhoff","year":"2005","journal-title":"Cell Death Differ."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1111\/j.1524-475X.2008.00415.x","article-title":"Multiplexed analysis of matrix metalloproteinases in leg ulcer tissue of patients with chronic venous insufficiency before and after compression therapy","volume":"16","author":"Beidler","year":"2008","journal-title":"Wound Repair Regen."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1111\/j.0022-202X.2005.23789.x","article-title":"Abnormal extracellular matrix metabolism in chronically ischemic skin: A mechanism for dermal failure in leg ulcers","volume":"125","author":"Dalton","year":"2005","journal-title":"J. Investig. Derm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1177\/1534734609331596","article-title":"Finding the culprit: A review of the influences of proteases on the chronic wound environment","volume":"8","author":"Rayment","year":"2009","journal-title":"Int. J. Low Extrem. Wounds"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1524-475X.2008.00436.x","article-title":"Wound healing essentials: Let there be oxygen","volume":"17","author":"Sen","year":"2009","journal-title":"Wound Repair Regen."},{"key":"ref_6","first-page":"599","article-title":"Effect of hypoxia on the expression of matrix metalloproteinase and tissue inhibitors of matrix metalloproteinase mRNA in human periodontal ligament fibroblasts in vitro","volume":"47","author":"Song","year":"2012","journal-title":"Zhonghua Kou Qiang Yi Xue Za Zhi"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1002\/dmrr.2742","article-title":"Disturbed hypoxic responses as a pathogenic mechanism of diabetic foot ulcers","volume":"32","author":"Catrina","year":"2016","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1002\/bdrc.21016","article-title":"Elastin signaling in wound repair","volume":"96","author":"Almine","year":"2012","journal-title":"Birth Defects Res. C Embryo Today"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s00268-003-6897-8","article-title":"Expression of elastic components in healthy and varicose veins","volume":"27","author":"Bujan","year":"2003","journal-title":"World J. Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1017\/S146239940600007X","article-title":"Elastic fibres in health and disease","volume":"8","author":"Kielty","year":"2006","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1267\/ahc.10026","article-title":"Fibulin-4 and -5, but not Fibulin-2, are Associated with Tropoelastin Deposition in Elastin-Producing Cell Culture","volume":"43","author":"Yamauchi","year":"2010","journal-title":"Acta Histochem. Cytochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1089\/rej.2008.0760","article-title":"Differential expression of lysyl oxidases LOXL1 and LOX during growth and aging suggests specific roles in elastin and collagen fiber remodeling in rat aorta","volume":"11","author":"Behmoaras","year":"2008","journal-title":"Rejuvenation Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1038\/ng1297","article-title":"Elastic fiber homeostasis requires lysyl oxidase-like 1 protein","volume":"36","author":"Liu","year":"2004","journal-title":"Nat. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"42848","DOI":"10.1074\/jbc.M506832200","article-title":"The Pro-regions of lysyl oxidase and lysyl oxidase-like 1 are required for deposition onto elastic fibers","volume":"280","author":"Thomassin","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.jbiomech.2012.12.019","article-title":"TGF-beta1 induces the different expressions of lysyl oxidases and matrix metalloproteinases in anterior cruciate ligament and medial collateral ligament fibroblasts after mechanical injury","volume":"46","author":"Xie","year":"2013","journal-title":"J. Biomech."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s00264-012-1549-y","article-title":"Interleukin-1 beta influences on lysyl oxidases and matrix metalloproteinases profile of injured anterior cruciate ligament and medial collateral ligament fibroblasts","volume":"37","author":"Xie","year":"2013","journal-title":"Int. Orthop."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/bdrc.20111","article-title":"New insights into elastic fiber assembly","volume":"81","author":"Wagenseil","year":"2007","journal-title":"Birth Defects Res. C Embryo Today"},{"key":"ref_18","first-page":"L566","article-title":"Hypoxia downregulates tropoelastin gene expression in rat lung fibroblasts by pretranslational mechanisms","volume":"277","author":"Berk","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1158\/0008-5472.CAN-10-1516","article-title":"The HIF-1-inducible lysyl oxidase activates HIF-1 via the Akt pathway in a positive regulation loop and synergizes with HIF-1 in promoting tumor cell growth","volume":"71","author":"Pez","year":"2011","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/nm.2844","article-title":"Asic3 is a neuronal mechanosensor for pressure-induced vasodilation that protects against pressure ulcers","volume":"18","author":"Fromy","year":"2012","journal-title":"Nat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1093\/molehr\/gal081","article-title":"What is the appropriate oxygen tension for in vitro culture?","volume":"12","author":"Sullivan","year":"2006","journal-title":"Mol. Hum. Reprod."},{"key":"ref_22","first-page":"1093","article-title":"Oxygen tension and cancer-cell culture: Half a century of artifacts?","volume":"24","author":"Wion","year":"2008","journal-title":"Med. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"35","DOI":"10.2147\/HP.S92198","article-title":"Frequently asked questions in hypoxia research","volume":"3","author":"Wenger","year":"2015","journal-title":"Hypoxia"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.jdermsci.2011.09.006","article-title":"Hypoxia regulates the expression of extracellular matrix associated proteins in equine dermal fibroblasts via HIF1","volume":"65","author":"Deschene","year":"2012","journal-title":"J. Derm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"L931","DOI":"10.1152\/ajplung.00037.2005","article-title":"Hypoxia suppresses elastin repair by rat lung fibroblasts","volume":"289","author":"Berk","year":"2005","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1046\/j.1524-475x.2000.00068.x","article-title":"Ischemia-reperfusion injury in chronic pressure ulcer formation: A skin model in the rat","volume":"8","author":"Peirce","year":"2000","journal-title":"Wound Repair Regen."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/S0022-4804(03)00227-0","article-title":"A novel murine model of cyclical cutaneous ischemia-reperfusion injury","volume":"116","author":"Reid","year":"2004","journal-title":"J. Surg. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1038\/sj.jid.5701258","article-title":"The loss of MCP-1 attenuates cutaneous ischemia-reperfusion injury in a mouse model of pressure ulcer","volume":"128","author":"Saito","year":"2008","journal-title":"J. Investig. Derm."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1111\/j.1524-475X.2007.00206.x","article-title":"Reduced up-regulation of cytoprotective genes in rat cutaneous tissue during the second cycle of ischemia-reperfusion","volume":"15","author":"Sisco","year":"2007","journal-title":"Wound Repair Regen."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1242\/jcs.115.14.2817","article-title":"Elastic fibres","volume":"115","author":"Kielty","year":"2002","journal-title":"J. Cell Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"23045","DOI":"10.1074\/jbc.M402656200","article-title":"Identification of a major microfibril-associated glycoprotein-1-binding domain in fibrillin-2","volume":"279","author":"Werneck","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1007\/s00424-007-0400-6","article-title":"Induction of carbonic anhydrase IX by hypoxia and chemical disruption of oxygen sensing in rat fibroblasts and cardiomyocytes","volume":"456","author":"Holotnakova","year":"2008","journal-title":"Pflug. Arch."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ymgme.2013.12.006","article-title":"Transcriptional profiling of the human fibrillin\/LTBP gene family, key regulators of mesenchymal cell functions","volume":"112","author":"Davis","year":"2014","journal-title":"Mol. Genet. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.cca.2008.05.002","article-title":"Regulation of gene expression by hypoxia: Integration of the HIF-transduced hypoxic signal at the hypoxia-responsive element","volume":"395","author":"Kaluz","year":"2008","journal-title":"Clin. Chim. Acta"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/s12031-017-0913-1","article-title":"MiR-9-5p Down-Regulates PiT2, but not PiT1 in Human Embryonic Kidney 293 Cells","volume":"62","author":"Bezerra","year":"2017","journal-title":"J. Mol. NeuroSci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"24553","DOI":"10.1074\/jbc.M109.019364","article-title":"Differential regulation of elastic fiber formation by fibulin-4 and -5","volume":"284","author":"Choudhury","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.2147\/OTT.S38110","article-title":"The potential for targeting extracellular LOX proteins in human malignancy","volume":"6","author":"Erler","year":"2013","journal-title":"Onco Targets"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1111\/j.0022-202X.2004.22330.x","article-title":"Lysyl oxidase-like and lysyl oxidase are present in the dermis and epidermis of a skin equivalent and in human skin and are associated to elastic fibers","volume":"122","author":"Noblesse","year":"2004","journal-title":"J. Investig. Derm."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Fhayli, W., Boete, Q., Kihal, N., Cenizo, V., Sommer, P., Boyle, W.A., Jacob, M.P., and Faury, G. (2020). Dill Extract Induces Elastic Fiber Neosynthesis and Functional Improvement in the Ascending Aorta of Aged Mice with Reversal of Age-Dependent Cardiac Hypertrophy and Involvement of Lysyl Oxidase-Like-1. Biomolecules, 10.","DOI":"10.3390\/biom10020173"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/jcp.20206","article-title":"A procollagen C-proteinase inhibitor diminishes collagen and lysyl oxidase processing but not collagen cross-linking in osteoblastic cultures","volume":"203","author":"Pischon","year":"2005","journal-title":"J. Cell Physiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1042\/EBC20180050","article-title":"Lysyl oxidases: From enzyme activity to extracellular matrix cross-links","volume":"63","author":"Vallet","year":"2019","journal-title":"Essays BioChem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"479","DOI":"10.3109\/03008207.2011.564337","article-title":"A novel proteolytic processing of prolysyl oxidase","volume":"52","author":"Atsawasuwan","year":"2011","journal-title":"Connect. Tissue Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"13294","DOI":"10.1074\/jbc.M109.088864","article-title":"Interaction between periostin and BMP-1 promotes proteolytic activation of lysyl oxidase","volume":"285","author":"Maruhashi","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"24400","DOI":"10.1074\/jbc.M003665200","article-title":"Interaction of tropoelastin with the amino-terminal domains of fibrillin-1 and fibrillin-2 suggests a role for the fibrillins in elastic fiber assembly","volume":"275","author":"Trask","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/labinvest.2010.49","article-title":"Enhanced fibrillin-2 expression is a general feature of wound healing and sclerosis: Potential alteration of cell attachment and storage of TGF-beta","volume":"90","author":"Brinckmann","year":"2010","journal-title":"Lab. Investig."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/aja.1001750409","article-title":"Collagen types I, III, and V in human embryonic and fetal skin","volume":"175","author":"Smith","year":"1986","journal-title":"Am. J. Anat."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/j.biocel.2003.12.002","article-title":"Tenascins","volume":"36","year":"2004","journal-title":"Int. J. BioChem. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/S0945-053X(02)00100-2","article-title":"Fibrillin-1 and fibrillin-2 in human embryonic and early fetal development","volume":"21","author":"Quondamatteo","year":"2002","journal-title":"Matrix Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1016\/j.biocel.2004.01.007","article-title":"Connective tissues: Signalling by tenascins","volume":"36","author":"Tucker","year":"2004","journal-title":"Int. J. BioChem. Cell Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1006\/abio.2001.5464","article-title":"A fluorometric assay for detection of lysyl oxidase enzyme activity in biological samples","volume":"300","author":"Palamakumbura","year":"2002","journal-title":"Anal. BioChem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.mvr.2013.10.001","article-title":"Skin microvascular response to pressure load in obese mice","volume":"90","author":"Begey","year":"2013","journal-title":"Microvasc. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1824\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:14:43Z","timestamp":1760134483000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1824"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,5]]},"references-count":51,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23031824"],"URL":"https:\/\/doi.org\/10.3390\/ijms23031824","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,5]]}}}