{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T09:58:39Z","timestamp":1773827919778,"version":"3.50.1"},"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T00:00:00Z","timestamp":1674000000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81570877"],"award-info":[{"award-number":["81570877"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81873682"],"award-info":[{"award-number":["81873682"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Objective<\/jats:title>\n<jats:p>To investigate the effects of scleral collagen cross-linking (SXL) using riboflavin and ultraviolet A (UVA) light on the scleral thickness of different regions and expression of matrix metalloproteinase 2 (MMP-2) and membrane-type MMP-1 (MT1-MMP) in guinea pigs with lens-induced myopia.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>Forty-eight 4-week-old guinea pigs were assigned to three groups (n = 16 per group): SXL group, lens-induced myopia (LIM) group, and control group. The sclera of the right eye of the guinea pig in the SXL group was surgically exposed, riboflavin was dropped on the treatment area for 10 minutes before the 30-minute UVA irradiation. The same surgical procedure was performed in the LIM group without UVA irradiation. The -10.00 D lenses were then placed on the right eyes of guinea pigs in the SXL and LIM groups for six weeks. The control group received no treatment. The left eyes were untreated in all groups. The ocular axial length (AXL) and refraction were measured at 4 weeks and 10 weeks of age. 10-week-old guinea pigs were sacrificed, and the right eyes were enucleated and evenly divided for preparation of hematoxylin and eosin (HE) stained sections, quantitative real-time polymerase chain reaction (qPCR) and western blotting. The scleral thickness of different regions was measured on HE stained sections. The temporal half of the sclera was harvested to measure the expression of MMP-2 and MT1-MMP by qPCR and western blotting.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>The AXL was significantly shorter, and the degree of myopic refraction was significantly lower in the SXL group than those in the LIM group at 10 weeks of age. The scleral thickness of the cross-linked area was significantly greater in the SXL group than that of the corresponding area in the LIM group, while the scleral thickness of the untreated nasal side was not significantly different between the SXL group and the LIM group. The expression of MMP-2 and MT1-MMP of the cross-linked sclera was significantly downregulated compared with that of the corresponding area in the LIM group.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Riboflavin\/UVA SXL could slow myopia progression and thicken the cross-linked sclera in guinea pigs, which might be related to the downregulation of MMP-2 and MT1-MMP expression during the scleral remodeling process.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0279111","type":"journal-article","created":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T18:44:35Z","timestamp":1674067475000},"page":"e0279111","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Effects of riboflavin\/ultraviolet-A scleral collagen cross-linking on regional scleral thickness and expression of MMP-2 and MT1-MMP in myopic guinea pigs"],"prefix":"10.1371","volume":"18","author":[{"given":"Xiaotong","family":"Lv","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingbo","family":"Lai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yushan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingshen","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6889-7729","authenticated-orcid":true,"given":"Yu","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanzheng","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ningli","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3715-4164","authenticated-orcid":true,"given":"Fengju","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,1,18]]},"reference":[{"issue":"5","key":"pone.0279111.ref001","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.ophtha.2016.01.006","article-title":"Global Prevalence of Myopia and High Myopia and Temporal Trends from 2000 through 2050","volume":"123","author":"BA Holden","year":"2016","journal-title":"Ophthalmology"},{"issue":"3","key":"pone.0279111.ref002","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S1350-9462(02)00063-0","article-title":"Role of the sclera in the development and pathological complications of myopia","volume":"22","author":"N. McBrien","year":"2003","journal-title":"Progress in Retinal and Eye Research"},{"issue":"12","key":"pone.0279111.ref003","first-page":"3713","article-title":"Scleral Remodeling during the Development of and Recovery from Axial Myopia in the Tree Shrew","volume":"41","author":"NA McBrien","year":"2000","journal-title":"Investigative Ophthalmology & Visual Science"},{"key":"pone.0279111.ref004","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.exer.2014.07.015","article-title":"The dynamic sclera: Extracellular matrix remodeling in normal ocular growth and myopia development","volume":"133","author":"AR Harper","year":"2015","journal-title":"Experimental Eye Research"},{"key":"pone.0279111.ref005","article-title":"The family of matrix metalloproteinases","volume":"732","author":"JE Woessner","year":"1994","journal-title":"Annu. NY. Acad"},{"issue":"11","key":"pone.0279111.ref006","doi-asserted-by":"crossref","first-page":"7414","DOI":"10.1073\/pnas.102185399","article-title":"Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2","volume":"99","author":"E Morgunova","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7","key":"pone.0279111.ref007","first-page":"1380","article-title":"Form-deprivation myopia induces activation of scleral matrix metalloproteinase-2 in tree shrew","volume":"37","author":"JA Guggenheim","year":"1996","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"5","key":"pone.0279111.ref008","doi-asserted-by":"crossref","first-page":"e96952","DOI":"10.1371\/journal.pone.0096952","article-title":"The sonic hedgehog signaling pathway induces myopic development by activating matrix metalloproteinase (MMP)-2 in Guinea pigs","volume":"9","author":"M Chen","year":"2014","journal-title":"PLoS One"},{"issue":"8","key":"pone.0279111.ref009","first-page":"1555","article-title":"Increased latent gelatinase activity in the sclera of visually deprived chicks","volume":"36","author":"JA Rada","year":"1995","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"13","key":"pone.0279111.ref010","first-page":"3091","article-title":"Gelatinase A and TIMP-2 expression in the fibrous sclera of myopic and recovering chick eyes","volume":"40","author":"JA Rada","year":"1999","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"6","key":"pone.0279111.ref011","doi-asserted-by":"crossref","first-page":"3922","DOI":"10.1167\/iovs.14-13983","article-title":"MMP-2, MMP-3, TIMP-1, TIMP-2, and TIMP-3 protein levels in human aqueous humor: relationship with axial length","volume":"55","author":"Y Jia","year":"2014","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"11","key":"pone.0279111.ref012","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1007\/s00417-014-2768-2","article-title":"Changes of TGF-\u03b22, MMP-2, and TIMP-2 levels in the vitreous of patients with high myopia","volume":"252","author":"H Zhuang","year":"2014","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"issue":"2","key":"pone.0279111.ref013","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/S0042-6989(98)00150-3","article-title":"Regulation of the mechanical properties of tree shrew sclera by the visual environment","volume":"39","author":"JJ Siegwart","year":"1999","journal-title":"Vision Res"},{"issue":"3","key":"pone.0279111.ref014","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1167\/iovs.14-15352","article-title":"Changing material properties of the tree shrew sclera during minus lens compensation and recovery","volume":"56","author":"R Grytz","year":"2015","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"pone.0279111.ref015","first-page":"818","article-title":"Bulk changes in posterior scleral collagen microstructure in human high myopia","volume":"24","author":"PP Markov","year":"2018","journal-title":"Mol Vis"},{"issue":"3","key":"pone.0279111.ref016","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1002\/jbm.a.32305","article-title":"Genipin enhances the mechanical properties of tissue-engineered cartilage and protects against inflammatory degradation when used as a medium supplement","volume":"91","author":"E Lima","year":"2009","journal-title":"J Biomed Mater Res A"},{"issue":"1","key":"pone.0279111.ref017","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.jcrs.2014.09.033","article-title":"Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: ten-year results","volume":"41","author":"F Raiskup","year":"2015","journal-title":"J Cataract Refract Surg"},{"issue":"4","key":"pone.0279111.ref018","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1111\/j.1600-0420.2005.00447.x","article-title":"Cross-linking of scleral collagen in the rabbit using riboflavin and UVA","volume":"83","author":"G Wollensak","year":"2005","journal-title":"Acta ophthalmologica Scandinavica"},{"issue":"2","key":"pone.0279111.ref019","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1111\/j.1755-3768.2008.01229.x","article-title":"Long-term biomechanical properties of rabbit sclera after collagen crosslinking using riboflavin and ultraviolet A (UVA)","volume":"87","author":"G Wollensak","year":"2009","journal-title":"Acta Ophthalmologica"},{"issue":"2","key":"pone.0279111.ref020","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.jtos.2013.01.002","article-title":"Corneal crosslinking with riboflavin and ultraviolet A. I. Principles","volume":"11","author":"F Raiskup","year":"2013","journal-title":"Ocul Surf"},{"key":"pone.0279111.ref021","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.exer.2014.07.019","article-title":"Scleral cross-linking using riboflavin and ultraviolet-a radiation for prevention of progressive myopia in a rabbit model","volume":"127","author":"A Dotan","year":"2014","journal-title":"Exp Eye Res"},{"issue":"11","key":"pone.0279111.ref022","article-title":"Scleral Cross-Linking Using Riboflavin UVA Irradiation for the Prevention of Myopia Progression in a Guinea Pig Model: Blocked Axial Extension and Altered Scleral Microstructure","volume":"11","author":"S Liu","year":"2016","journal-title":"Plos One"},{"issue":"9","key":"pone.0279111.ref023","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1016\/0042-6989(94)00243-F","article-title":"Reduced extracellular matrix in mammalian sclera with induced myopia","volume":"35","author":"TT Norton","year":"1995","journal-title":"Vision Res"},{"issue":"10","key":"pone.0279111.ref024","first-page":"2179","article-title":"Structural and ultrastructural changes to the sclera in a mammalian model of high myopia","volume":"42","author":"NA McBrien","year":"2001","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"4","key":"pone.0279111.ref025","doi-asserted-by":"crossref","first-page":"2720","DOI":"10.1167\/iovs.14-15631","article-title":"Scleral Thickness in Chinese Eyes","volume":"56","author":"L S","year":"2015","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"5","key":"pone.0279111.ref026","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1007\/s10103-012-1237-6","article-title":"Structural response of human corneal and scleral tissues to collagen cross-linking treatment with riboflavin and ultraviolet A light","volume":"28","author":"S Choi","year":"2012","journal-title":"Lasers in Medical Science"},{"issue":"8","key":"pone.0279111.ref027","first-page":"2050","article-title":"Decreased proteoglycan synthesis associated with form deprivation myopia in mature primate eyes","volume":"41","author":"JA Rada","year":"2000","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"13","key":"pone.0279111.ref028","doi-asserted-by":"crossref","first-page":"9684","DOI":"10.1167\/iovs.11-7894","article-title":"Quantitative mapping of scleral fiber orientation in normal rat eyes","volume":"52","author":"MJ Girard","year":"2011","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"pone.0279111.ref029","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.exer.2017.07.002","article-title":"Iontophoresis-assisted accelerated riboflavin\/ultraviolet A scleral cross-linking: A potential treatment for pathologic myopia","volume":"162","author":"S Rong","year":"2017","journal-title":"Exp Eye Res"},{"issue":"2","key":"pone.0279111.ref030","doi-asserted-by":"crossref","DOI":"10.1167\/iovs.12-11277","article-title":"Resistance of Corneal RFUVA\u2013Cross-Linked Collagens and Small Leucine-Rich Proteoglycans to Degradation by Matrix Metalloproteinases","volume":"54","author":"Y Zhang","year":"2013","journal-title":"Investigative Opthalmology & Visual Science"},{"issue":"2","key":"pone.0279111.ref031","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.visres.2008.10.008","article-title":"Spectacle lens compensation in the pigmented guinea pig","volume":"49","author":"MH Howlett","year":"2009","journal-title":"Vision Res"},{"issue":"1","key":"pone.0279111.ref032","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.exer.2009.02.019","article-title":"Axial myopia induced by hyperopic defocus in guinea pigs: A detailed assessment on susceptibility and recovery","volume":"89","author":"F Lu","year":"2009","journal-title":"Experimental Eye Research"},{"issue":"2","key":"pone.0279111.ref033","doi-asserted-by":"crossref","first-page":"e0192718","DOI":"10.1371\/journal.pone.0192718","article-title":"Study of retina and choroid biological parameters of rhesus monkeys eyes on scleral collagen cross-linking by riboflavin and ultraviolet A","volume":"13","author":"M Sun","year":"2018","journal-title":"PLoS One"},{"issue":"2","key":"pone.0279111.ref034","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1111\/ceo.12392","article-title":"Safety evaluation of rabbit eyes on scleral collagen cross-linking by riboflavin and ultraviolet A","volume":"43","author":"M Wang","year":"2015","journal-title":"Clinical & Experimental Ophthalmology"},{"issue":"5","key":"pone.0279111.ref035","doi-asserted-by":"crossref","first-page":"333","DOI":"10.3928\/1081597X-20190410-03","article-title":"Early Changes of Ocular Biological Parameters in Rhesus Monkeys After Scleral Cross-linking With Riboflavin\/Ultraviolet-A","volume":"35","author":"BW Ouyang","year":"2019","journal-title":"Journal of refractive surgery (Thorofare, NJ: 1995)"},{"issue":"10","key":"pone.0279111.ref036","doi-asserted-by":"crossref","first-page":"696","DOI":"10.3928\/1081597X-20200807-01","article-title":"Evaluation of the Safety and Long-term Scleral Biomechanical Stability of UVA Cross-linking on Scleral Collagen in Rhesus Monkeys","volume":"36","author":"M Sun","year":"2020","journal-title":"Journal of refractive surgery (Thorofare, NJ: 1995)"},{"issue":"11","key":"pone.0279111.ref037","first-page":"5872","article-title":"Matrix metalloproteinase-2 is an interstitial collagenase. Inhibitor-free enzyme catalyzes the cleavage of collagen fibrils and soluble native type I collagen generating the specific 3\/4- and 1\/4-length fragments","volume":"270","author":"RT Aimes","year":"1995","journal-title":"J Biol Chem"},{"key":"pone.0279111.ref038","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1146\/annurev.cellbio.17.1.463","article-title":"How matrix metalloproteinases regulate cell behavior","volume":"17","author":"MD Sternlicht","year":"2001","journal-title":"Annu Rev Cell Dev Biol"},{"issue":"10","key":"pone.0279111.ref039","doi-asserted-by":"crossref","first-page":"3484","DOI":"10.1167\/iovs.05-0194","article-title":"Selective regulation of MMP and TIMP mRNA levels in tree shrew sclera during minus lens compensation and recovery","volume":"46","author":"JT Siegwart","year":"2005","journal-title":"Invest Ophthalmol Vis Sci"},{"issue":"4","key":"pone.0279111.ref040","doi-asserted-by":"crossref","first-page":"2446","DOI":"10.1074\/jbc.272.4.2446","article-title":"Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules","volume":"272","author":"E Ohuchi","year":"1997","journal-title":"J Biol Chem"},{"issue":"3","key":"pone.0279111.ref041","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1111\/j.1432-1033.1997.00751.x","article-title":"Membrane-type matrix metalloproteinases 1 and 2 exhibit broad-spectrum proteolytic capacities comparable to many matrix metalloproteinases","volume":"250","author":"MP d\u2019Ortho","year":"1997","journal-title":"Eur J Biochem"},{"key":"pone.0279111.ref042","doi-asserted-by":"crossref","unstructured":"Fini ME, Cook JR, Mohan R, Brinckerhoff CE. Regulation of Matrix Metalloproteinase Gene Expression: Matrix Metalloproteinases; 1998.","DOI":"10.1016\/B978-012545090-4\/50013-6"},{"issue":"3","key":"pone.0279111.ref043","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.dental.2015.12.012","article-title":"Use of crosslinkers to inactivate dentin MMPs","volume":"32","author":"R Seseogullari-Dirihan","year":"2016","journal-title":"Dent Mater"},{"issue":"12","key":"pone.0279111.ref044","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1177\/0022034511423397","article-title":"Effect of UVA-activated riboflavin on dentin bonding","volume":"90","author":"A Cova","year":"2011","journal-title":"J Dent Res"},{"key":"pone.0279111.ref045","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.exer.2017.08.019","article-title":"Riboflavin and ultraviolet A irradiation for the prevention of progressive myopia in a guinea pig model","volume":"165","author":"X Li","year":"2017","journal-title":"Experimental Eye Research"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0279111","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,18]],"date-time":"2023-01-18T18:45:23Z","timestamp":1674067523000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0279111"}},"subtitle":[],"editor":[{"given":"Zhongjun","family":"Zhou","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,1,18]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1,18]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0279111","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,18]]}}}