{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T16:06:31Z","timestamp":1772813191227,"version":"3.50.1"},"reference-count":43,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T00:00:00Z","timestamp":1628812800000},"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":["EY021725"],"award-info":[{"award-number":["EY021725"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY028888"],"award-info":[{"award-number":["EY028888"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY023202"],"award-info":[{"award-number":["EY023202"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Keratoconus (KC) is a common corneal ectatic disease that affects 1:500\u20131:2000 people worldwide and is associated with a progressive thinning of the corneal stroma that may lead to severe astigmatism and visual deficits. Riboflavin-mediated collagen crosslinking currently remains the only approved treatment to halt progressive corneal thinning associated with KC by improving the biomechanical properties of the stroma. Treatments designed to increase collagen deposition by resident corneal stromal keratocytes remain elusive. In this study, we evaluated the effects of arginine supplementation on steady-state levels of arginine and arginine-related metabolites (e.g., ornithine, proline, hydroxyproline, spermidine, and putrescine) and collagen protein expression by primary human corneal fibroblasts isolated from KC and non-KC (healthy) corneas and cultured in an established 3D in vitro model. We identified lower cytoplasmic arginine and spermidine levels in KC-derived constructs compared to healthy controls, which corresponded with overall higher gene expression of arginase. Arginine supplementation led to a robust increase in cytoplasmic arginine, ornithine, and spermidine levels in controls only and a significant increase in collagen type I secretion in KC-derived constructs. Further studies evaluating safety and efficacy of arginine supplementation are required to elucidate the potential therapeutic applications of modulating collagen deposition in the context of KC.<\/jats:p>","DOI":"10.3390\/cells10082076","type":"journal-article","created":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T05:34:46Z","timestamp":1628832886000},"page":"2076","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Arginine Supplementation Promotes Extracellular Matrix and Metabolic Changes in Keratoconus"],"prefix":"10.3390","volume":"10","author":[{"given":"Tina B.","family":"McKay","sequence":"first","affiliation":[{"name":"Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shrestha","family":"Priyadarsini","sequence":"additional","affiliation":[{"name":"Dean McGee Eye Institute, Oklahoma City, OK 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tyler","family":"Rowsey","sequence":"additional","affiliation":[{"name":"Dean McGee Eye Institute, Oklahoma City, OK 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitrios","family":"Karamichos","sequence":"additional","affiliation":[{"name":"North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"},{"name":"Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"},{"name":"Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1126\/science.130.3373.432","article-title":"Amino acid metabolism in mammalian cell cultures","volume":"130","author":"Eagle","year":"1959","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0003-9861(91)90097-3","article-title":"Enzymological evidence for the indispensability of small intestine in the synthesis of arginine from glutamate: I. 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