Growth Differentiation Factor-15-Induced Contractile Activity and Extracellular Matrix Production in Human Trabecular Meshwork Cells.

Journal Article (Journal Article)

PURPOSE: To determine the role and regulation of growth differentiation factor-15 (GDF-15), a TGF-β-related cytokine in human trabecular meshwork (TM) cells in the context of aqueous humor (AH) outflow and IOP. METHODS: Regulation of expression by external cues, and the distribution and secretion of GDF-15 by human TM primary cell cultures, and the effects of recombinant (r) GDF-15 on TM cell contractile characteristics, actin cytoskeleton, cell adhesion, extracellular matrix (ECM), α-smooth muscle actin (αSMA), SMAD signaling, and gene expression were determined by immunoblot, immunofluorescence, mass spectrometry, cDNA microarray, and real-time quantitative PCR (RT-qPCR) analyses. RESULTS: Growth differentiation factor-15, a common constituent of ECM derived from the human TM cells, was confirmed to be distributed throughout the conventional aqueous humor outflow pathway of the human eye. Growth differentiation factor-15 protein levels were significantly increased in human TM cells in response to TGF-β2, dexamethasone, endothelin-1, lysophosphatidic acid, TNF-α, IL-1β treatment, and by cyclic mechanical stretch. Stimulation of human TM cells with rGDF-15 caused a significant increase in the formation of actin stress fibers and focal adhesions, myosin light chain phosphorylation, SMAD signaling, gene expression, and the levels of αSMA and ECM proteins. CONCLUSIONS: The results of this study, including a robust induction of GDF-15 expression by several external factors known to elevate IOP, and rGDF-15-induced increase in contractility, cell adhesion, and the levels of ECM proteins and αSMA in TM cells, collectively suggest a potential role for GDF-15 in homeostasis and dysregulation of AH outflow and IOP in normal and glaucomatous eyes, respectively.

Full Text

Duke Authors

Cited Authors

  • Muralidharan, AR; Maddala, R; Skiba, NP; Rao, PV

Published Date

  • December 1, 2016

Published In

Volume / Issue

  • 57 / 15

Start / End Page

  • 6482 - 6495

PubMed ID

  • 27918822

Pubmed Central ID

  • PMC5152563

Electronic International Standard Serial Number (EISSN)

  • 1552-5783

Digital Object Identifier (DOI)

  • 10.1167/iovs.16-20671


  • eng

Conference Location

  • United States