{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T22:52:09Z","timestamp":1777330329665,"version":"3.51.4"},"reference-count":61,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T00:00:00Z","timestamp":1583280000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY027083,EY026181,P30EY025585,T32EY024236,EY022768"],"award-info":[{"award-number":["EY027083,EY026181,P30EY025585,T32EY024236,EY022768"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"publisher","award":["Challenge Grant and Lew Wasserman Award"],"award-info":[{"award-number":["Challenge Grant and Lew Wasserman Award"]}],"id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007312","name":"Cleveland Clinic Foundation","doi-asserted-by":"publisher","award":["Department Funds"],"award-info":[{"award-number":["Department Funds"]}],"id":[{"id":"10.13039\/100007312","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Sorsby\u2019s fundus dystrophy (SFD) is an inherited blinding disorder caused by mutations in the tissue inhibitor of metalloproteinase-3 (TIMP3) gene. The SFD pathology of macular degeneration with subretinal deposits and choroidal neovascularization (CNV) closely resembles that of the more common age-related macular degeneration (AMD). The objective of this study was to gain further insight into the molecular mechanism(s) by which mutant TIMP3 induces CNV. In this study we demonstrate that hyaluronan (HA), a large glycosaminoglycan, is elevated in the plasma and retinal pigment epithelium (RPE)\/choroid of patients with AMD. Mice carrying the S179C-TIMP3 mutation also showed increased plasma levels of HA as well as accumulation of HA around the RPE in the retina. Human RPE cells expressing the S179C-TIMP3 mutation accumulated HA apically, intracellularly and basally when cultured long-term compared with cells expressing wildtype TIMP3. We recently reported that RPE cells carrying the S179C-TIMP3 mutation have the propensity to induce angiogenesis via basic fibroblast growth factor (FGF-2). We now demonstrate that FGF-2 induces accumulation of HA in RPE cells. These results suggest that the TIMP3-MMP-FGF-2-HA axis may have an important role in the pathogenesis of CNV in SFD and possibly AMD.<\/jats:p>","DOI":"10.3390\/cells9030608","type":"journal-article","created":{"date-parts":[[2020,3,4]],"date-time":"2020-03-04T10:46:08Z","timestamp":1583318768000},"page":"608","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Role of FGF and Hyaluronan in Choroidal Neovascularization in Sorsby Fundus Dystrophy"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1613-0251","authenticated-orcid":false,"given":"Alyson","family":"Wolk","sequence":"first","affiliation":[{"name":"Cole Eye Institute &amp; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA"},{"name":"Cleveland Clinic Lerner College of Medicine, Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2083-1293","authenticated-orcid":false,"given":"Dilara","family":"Hatipoglu","sequence":"additional","affiliation":[{"name":"Cole Eye Institute &amp; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alecia","family":"Cutler","sequence":"additional","affiliation":[{"name":"Cole Eye Institute &amp; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariya","family":"Ali","sequence":"additional","affiliation":[{"name":"Cole Eye Institute &amp; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lestella","family":"Bell","sequence":"additional","affiliation":[{"name":"Cole Eye Institute &amp; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA"},{"name":"Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Department of Ophthalmology, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Hua Qi","sequence":"additional","affiliation":[{"name":"Cole Eye Institute &amp; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0938-9388","authenticated-orcid":false,"given":"Rupesh","family":"Singh","sequence":"additional","affiliation":[{"name":"Cole Eye Institute &amp; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Batoki","sequence":"additional","affiliation":[{"name":"Cole Eye Institute &amp; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Karle","sequence":"additional","affiliation":[{"name":"Cole Eye Institute &amp; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vera L.","family":"Bonilha","sequence":"additional","affiliation":[{"name":"Cole Eye Institute &amp; Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA"},{"name":"Cleveland Clinic Lerner College of Medicine, Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH 44195, USA"},{"name":"Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Department of Ophthalmology, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6440-7975","authenticated-orcid":false,"given":"Oliver","family":"Wessely","sequence":"additional","affiliation":[{"name":"Cleveland Clinic Lerner College of Medicine, Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH 44195, USA"},{"name":"Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1508-0731","authenticated-orcid":false,"given":"Heidi","family":"Stoehr","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent","family":"Hascall","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4845-9094","authenticated-orcid":false,"given":"Bela","family":"Anand-Apte","sequence":"additional","affiliation":[{"name":"Cole Eye Institute &amp; 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