Dexamethasone stiffens trabecular meshwork, trabecular meshwork cells, and matrix

Vijay Krishna Raghunathan, Joshua T. Morgan, Shin Ae Park, Darren Weber, Brett S. Phinney, Christopher J Murphy, Paul Russell

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

PURPOSE. Treatment with corticosteroids can result in ocular hypertension and may lead to the development of steroid-induced glaucoma. The extent to which biomechanical changes in trabecular meshwork (TM) cells and extracellular matrix (ECM) contribute toward this dysfunction is poorly understood. METHODS. Primary human TM (HTM) cells were cultured for either 3 days or 4 weeks in the presence or absence of dexamethasone (DEX), and cell mechanics, matrix mechanics and proteomics were determined, respectively. Adult rabbits were treated topically with either 0.1% DEX or vehicle over 3 weeks, and mechanics of the TM were determined. RESULTS. Treatment with DEX for 3 days resulted in a 2-fold increase in HTM cell stiffness, and this correlated with activation of extracellular signal-related kinase 1/2 (ERK1/2) and overexpression of α-smooth muscle actin (αSMA). Further, the matrix deposited by HTM cells chronically treated with DEX is approximately 4-fold stiffer, more organized, and has elevated expression of matrix proteins commonly implicated in glaucoma (decorin, myocilin, fibrillin, secreted frizzle-related protein [SFRP1], matrix-gla). Also, DEX treatment resulted in a 3.5-fold increase in stiffness of the rabbit TM. DISCUSSION. This integrated approach clearly demonstrates that DEX treatment increases TM cell stiffness concurrent with elevated αSMA expression and activation of the mitogenactivated protein kinase (MAPK) pathway, stiffens the ECM in vitro along with upregulation of Wnt antagonists and fibrotic markers embedded in a more organized matrix, and increases the stiffness of TM tissues in vivo. These results demonstrate glucocorticoid treatment can initiate the biophysical alteration associated with increased resistance to aqueous humor outflow and the resultant increase in IOP.

Original languageEnglish (US)
Pages (from-to)4447-4459
Number of pages13
JournalInvestigative Ophthalmology and Visual Science
Volume56
Issue number8
DOIs
StatePublished - 2015

Keywords

  • Cell and matrix mechanics
  • Elastic modulus
  • Extracellular matrix
  • Proteomics
  • Steroid-induced glaucoma

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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