{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T18:26:24Z","timestamp":1783794384015,"version":"3.55.0"},"reference-count":57,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,18]],"date-time":"2021-09-18T00:00:00Z","timestamp":1631923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 EY028616; EY026177"],"award-info":[{"award-number":["R01 EY028616; EY026177"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ocular hypertension (OHT) is a serious adverse effect of the widely prescribed glucocorticoid (GC) therapy and, if left undiagnosed, it can lead to glaucoma and complete blindness. Previously, we have shown that the small chemical chaperone, sodium-4-phenylbutyrate (PBA), rescues GC-induced OHT by reducing ocular endoplasmic reticulum (ER) stress. However, the exact mechanism of how PBA rescues GC-induced OHT is not completely understood. The trabecular meshwork (TM) is a filter-like specialized contractile tissue consisting of TM cells embedded within extracellular matrix (ECM) that controls intraocular pressure (IOP) by constantly regulating aqueous humor (AH) outflow. Induction of abnormal ECM deposition in TM is a hallmark of GC-induced OHT. Here, we investigated whether PBA reduces GC-induced OHT by degrading abnormal ECM deposition in TM using mouse model of GC-induced OHT, ex vivo cultured human TM tissues and primary human TM cells. We show that topical ocular eye drops of PBA (1%) significantly lowers elevated IOP in mouse model of GC-induced OHT. Importantly, PBA prevents synthesis and deposition of GC-induced ECM in TM. We report for the first time that PBA can degrade existing abnormal ECM in normal human TM cells\/tissues by inducing matrix metalloproteinase (MMP)9 expression and activity. Furthermore, inhibition of MMPs activity by chemical-inhibitor (minocycline) abrogated PBA\u2019s effect on ECM reduction and its associated ER stress. Our study indicates a non-chaperone activity of PBA via activation of MMP9 that degrades abnormal ECM accumulation in TM.<\/jats:p>","DOI":"10.3390\/ijms221810095","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T08:04:23Z","timestamp":1632211463000},"page":"10095","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Sodium 4-Phenylbutyrate Reduces Ocular Hypertension by Degrading Extracellular Matrix Deposition via Activation of MMP9"],"prefix":"10.3390","volume":"22","author":[{"given":"Prabhavathi","family":"Maddineni","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramesh B.","family":"Kasetti","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4956-841X","authenticated-orcid":false,"given":"Bindu","family":"Kodati","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Yacoub","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7823-2595","authenticated-orcid":false,"given":"Gulab S.","family":"Zode","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.exer.2015.06.002","article-title":"Animal models of glucocorticoid-induced glaucoma","volume":"141","author":"Overby","year":"2015","journal-title":"Exp. Eye Res."},{"key":"ref_2","unstructured":"Feroze, K.B., and Khazaeni, L. (2021). Steroid Induced Glaucoma, StatPearls."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"439","DOI":"10.2165\/00002512-199915060-00004","article-title":"Corticosteroids and Glaucoma Risk","volume":"15","author":"Tripathi","year":"1999","journal-title":"Drugs Aging"},{"key":"ref_4","first-page":"2485","article-title":"Corticosteroids and the risk of glaucoma","volume":"149","author":"Hardus","year":"2005","journal-title":"Ned Tijdschr Geneeskd."},{"key":"ref_5","first-page":"163","article-title":"Corticosteroid-induced ocular hypertension and glaucoma: A brief review and update of the literature","volume":"17","author":"Jones","year":"2006","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/sj.eye.6701895","article-title":"Corticosteroid-induced glaucoma: A review of the literature","volume":"20","author":"Kersey","year":"2006","journal-title":"Eye"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.survophthal.2020.01.002","article-title":"Steroid-induced glaucoma: Epidemiology, pathophysiology, and clinical management","volume":"65","author":"Roberti","year":"2020","journal-title":"Surv. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1001\/archopht.1963.00960050484010","article-title":"Effect of Corticosteroids on Intraocular Pressure and Fluid Dynamics. I. The Effect of Dexamethasone in the Normal Eye","volume":"70","author":"Armaly","year":"1963","journal-title":"Arch. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1001\/archopht.1963.00960050494011","article-title":"Effect of Corticosteroids on Intraocular Pressure and Fluid Dynamics. Ii. The Effect of Dexamethasone in the Glaucomatous Eye","volume":"70","author":"Armaly","year":"1963","journal-title":"Arch. Ophthalmol."},{"key":"ref_10","first-page":"353","article-title":"Steroid-induced glaucoma: A. Persistent elevation of intraocular pressure B. Histopathological aspects","volume":"75","author":"Spaeth","year":"1977","journal-title":"Trans. Am. Ophthalmol. Soc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-020-00400-9","article-title":"CNS axonal degeneration and transport deficits at the optic nerve head precede structural and functional loss of retinal ganglion cells in a mouse model of glaucoma","volume":"15","author":"Maddineni","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"14951","DOI":"10.1038\/s41598-017-14938-0","article-title":"Increased synthesis and deposition of extracellular matrix proteins leads to endoplasmic reticulum stress in the trabecular meshwork","volume":"7","author":"Kasetti","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9854","DOI":"10.1074\/jbc.RA118.002540","article-title":"Transforming growth factor beta2 (TGFbeta2) signaling plays a key role in glucocorticoid-induced ocular hypertension","volume":"293","author":"Kasetti","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.ajpath.2016.12.003","article-title":"Dexamethasone-Induced Ocular Hypertension in Mice: Effects of Myocilin and Route of Administration","volume":"187","author":"Patel","year":"2017","journal-title":"Am. J. Pathology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3860","DOI":"10.1167\/iovs.14-16220","article-title":"Increased Endoplasmic Reticulum Stress in Human Glaucomatous Trabecular Meshwork Cells and Tissues","volume":"56","author":"Peters","year":"2015","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.exer.2014.07.014","article-title":"Extracellular matrix in the trabecular meshwork: Intraocular pressure regulation and dysregulation in glaucoma","volume":"133","author":"Vranka","year":"2015","journal-title":"Exp. Eye Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.exer.2016.07.011","article-title":"Trabecular meshwork stiffness in glaucoma","volume":"158","author":"Wang","year":"2017","journal-title":"Exp. Eye Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1956","DOI":"10.1172\/JCI69774","article-title":"Ocular-specific ER stress reduction rescues glaucoma in murine glucocorticoid-induced glaucoma","volume":"124","author":"Zode","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_19","first-page":"478","article-title":"Dexamethasone-induced ocular hypertension in perfusion-cultured human eyes","volume":"36","author":"Clark","year":"1995","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_20","first-page":"1162","article-title":"TIMP1, TIMP2, and TIMP4 are increased in aqueous humor from primary open angle glaucoma patients","volume":"21","author":"Briggs","year":"2015","journal-title":"Mol. Vis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/1096-9896(2000)9999:9999<::AID-PATH670>3.0.CO;2-1","article-title":"Increased TIMP\/MMP ratio in varicose veins: A possible explanation for extracellular matrix accumulation","volume":"192","author":"Verbeuren","year":"2000","journal-title":"J. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/eye.2000.92","article-title":"Synthesis pattern of matrix metalloproteinases (MMPs) and inhibitors (TIMPs) in human explant organ cultures after treatment with latanoprost and dexamethasone","volume":"14","author":"Eckhardt","year":"2000","journal-title":"Eye"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Nga, A.D., Yap, S.-L., Samsudin, A., Abdul-Rahman, P.S., Hashim, O.H., and Mimiwati, Z. (2014). Matrix metalloproteinases and tissue inhibitors of metalloproteinases in the aqueous humour of patients with primary angle closure glaucoma\u2014a quantitative study. BMC Ophthalmol., 14.","DOI":"10.1186\/1471-2415-14-33"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1089\/jop.2019.0146","article-title":"Matrix Metalloproteinases and Glaucoma Treatment","volume":"36","author":"Weinreb","year":"2020","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1016\/j.actbio.2018.02.037","article-title":"Glaucomatous cell derived matrices differentially modulate non-glaucomatous trabecular meshwork cellular behavior","volume":"71","author":"Raghunathan","year":"2018","journal-title":"Acta Biomater."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1167\/iovs.11-8837","article-title":"Topical Ocular Sodium 4-Phenylbutyrate Rescues Glaucoma in a Myocilin Mouse Model of Primary Open-Angle Glaucoma","volume":"53","author":"Zode","year":"2012","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.ymgme.2010.03.014","article-title":"Phase 2 comparison of a novel ammonia scavenging agent with sodium phenylbutyrate in patients with urea cycle disorders: Safety, pharmacokinetics and ammonia control","volume":"100","author":"Lee","year":"2010","journal-title":"Mol. Genet. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1038\/npp.2008.229","article-title":"Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer\u2019s disease mouse model","volume":"34","author":"Ricobaraza","year":"2009","journal-title":"Neuropsychopharmacology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1080\/09273948.2019.1609049","article-title":"Alteration of MCP-1 and MMP-9 in Aqueous Humor Is Associated with Secondary Glaucoma in Fuchs Uveitis Syndrome","volume":"28","author":"Bauer","year":"2020","journal-title":"Ocul. Immunol. Inflamm."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Thakur, N., Kupani, M., Pandey, R., Mannan, R., Pruthi, A., and Mehrotra, S. (2018). Genetic association of \u22121562C > T polymorphism in the MMP9 gene with primary glaucoma in a north Indian population. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0192636"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1167\/iovs.18-26383","article-title":"Glucocorticoid Receptor Transactivation Is Required for Glucocorticoid-Induced Ocular Hypertension and Glaucoma","volume":"60","author":"Patel","year":"2019","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1167\/iovs.10-5598","article-title":"In vivo ocular efficacy profile of mapracorat, a novel selective glucocorticoid receptor agonist, in rabbit models of ocular disease","volume":"52","author":"Shafiee","year":"2011","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/j.exer.2008.10.004","article-title":"The role of steroids in outflow resistance","volume":"88","author":"Clark","year":"2009","journal-title":"Exp. Eye. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"67","DOI":"10.5005\/jp-journals-10028-1226","article-title":"Steroid-induced Glaucoma: An Avoidable Irreversible Blindness","volume":"11","author":"Phulke","year":"2017","journal-title":"J. Curr. Glaucoma Pract."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s00417-017-3773-z","article-title":"DEX implant intravitreal injection, sustained intraocular hypertension, and steroid-induced glaucoma in patients with no risk factors","volume":"256","author":"Rezkallah","year":"2018","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1167\/iovs.11-9314","article-title":"Elastic modulus determination of normal and glaucomatous human trabecular meshwork","volume":"53","author":"Russell","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1073\/pnas.1814889116","article-title":"In vivo measurement of trabecular meshwork stiffness in a corticosteroid-induced ocular hypertensive mouse model","volume":"116","author":"Li","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"26555","DOI":"10.1073\/pnas.1911837116","article-title":"Increased stiffness and flow resistance of the inner wall of Schlemm\u2019s canal in glaucomatous human eyes","volume":"116","author":"Vahabikashi","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4809","DOI":"10.1167\/iovs.17-22175","article-title":"Estimating Human Trabecular Meshwork Stiffness by Numerical Modeling and Advanced OCT Imaging","volume":"58","author":"Wang","year":"2017","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7756","DOI":"10.1167\/iovs.13-13088","article-title":"MMPs in the trabecular meshwork: Promising targets for future glaucoma therapies?","volume":"54","author":"Dekeyster","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1093\/hmg\/ddx028","article-title":"Therapeutic potential of AAV-mediated MMP-3 secretion from corneal endothelium in treating glaucoma","volume":"26","author":"Crosbie","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_42","first-page":"2649","article-title":"Effect of matrix metalloproteinases activity on outflow in perfused human organ culture","volume":"39","author":"Bradley","year":"1998","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"537","DOI":"10.3109\/02713689508998400","article-title":"Early changes in matrix metalloproteinases and inhibitors after in vitro laser treatment to the trabecular meshwork","volume":"14","author":"Parshley","year":"1995","journal-title":"Curr. Eye Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3309","DOI":"10.1167\/iovs.12-11362","article-title":"Overexpression of SPARC in Human Trabecular Meshwork Increases Intraocular Pressure and Alters Extracellular Matrix","volume":"54","author":"Oh","year":"2013","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_45","first-page":"1175","article-title":"Hyaluronic acid increases MMP-2 and MMP-9 expressions in cultured trabecular meshwork cells from patients with primary open-angle glaucoma","volume":"18","author":"Guo","year":"2012","journal-title":"Mol. Vis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5984","DOI":"10.1167\/iovs.16-19734","article-title":"Aberrant Collagen Composition of the Trabecular Meshwork Results in Reduced Aqueous Humor Drainage and Elevated IOP in MMP-9 Null Mice","volume":"57","author":"Andries","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1152\/physiol.00029.2013","article-title":"Matrix Metalloproteinase-9: Many Shades of Function in Cardiovascular Disease","volume":"28","author":"Yabluchanskiy","year":"2013","journal-title":"Physiology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1006\/exer.1993.1148","article-title":"Corticosteroid Treatment and Trabecular Meshwork Proteases in Cell and Organ Culture Supernatants","volume":"57","author":"Snyder","year":"1993","journal-title":"Exp. Eye Res."},{"key":"ref_49","first-page":"1362","article-title":"Sigma1 recognition sites in rabbit iris-ciliary body: Topical sigma1-site agonists lower intraocular pressure","volume":"289","author":"Bucolo","year":"1999","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4940","DOI":"10.1007\/s12035-017-0697-x","article-title":"The Sigma-1 Receptor Antagonist, S1RA, Reduces Stroke Damage, Ameliorates Post-Stroke Neurological Deficits and Suppresses the Overexpression of MMP-9","volume":"55","author":"Sanchez","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ophtha.2015.09.005","article-title":"Comparative Effectiveness of First-Line Medications for Primary Open-Angle Glaucoma: A Systematic Review and Network Meta-analysis","volume":"123","author":"Li","year":"2016","journal-title":"Ophthalmology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1006\/mthe.2002.0639","article-title":"Evidence of CFTR Function in Cystic Fibrosis after Systemic Administration of 4-Phenylbutyrate","volume":"6","author":"Zeitlin","year":"2002","journal-title":"Mol. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.exer.2016.07.009","article-title":"The many faces of the trabecular meshwork cell","volume":"158","author":"Stamer","year":"2017","journal-title":"Exp. Eye Res."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Kasetti, R.B., Patel, P.D., Maddineni, P., and Zode, G.S. (2020). Ex-vivo cultured human corneoscleral segment model to study the effects of glaucoma factors on trabecular meshwork. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0238408"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1186\/s12859-017-1934-z","article-title":"ImageJ2: ImageJ for the next generation of scientific image data","volume":"18","author":"Rueden","year":"2017","journal-title":"BMC Bioinform."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/978-1-4939-7407-8_12","article-title":"Methods for Analyzing Endoplasmic Reticulum Stress in the Trabecular Meshwork of Glaucoma Models","volume":"1695","author":"Maddineni","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"ref_57","unstructured":"GraphPad Software (2021). GraphPad Prism Version 9.00 for Windows, GraphPad Software."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/10095\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:01:50Z","timestamp":1760166110000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/10095"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,18]]},"references-count":57,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms221810095"],"URL":"https:\/\/doi.org\/10.3390\/ijms221810095","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,18]]}}}