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Mechanism of Fibronectin Binding to Human Trabecular Meshwork Exosomes and Its Modulation by Dexamethasone.

Publication ,  Journal Article
Dismuke, WM; Klingeborn, M; Stamer, WD
Published in: PLoS One
2016

Exosomes are emerging as important mediators of cell-matrix interactions by means of specific adhesion proteins. Changes in the tissue-specific exosomal protein expression may underlie pathological conditions whereby extracellular matrix turnover and homeostasis is disrupted. Ocular hypertension due to extracellular matrix accumulation in the trabecular meshwork is a hallmark of glucocorticoid-induced glaucoma. In the trabecular meshwork, exosomal fibronectin mediates cell matrix interactions at cellular structures called "invadosomes". Trabecular meshwork cells use invadosomes to turn over their surrounding matrix and maintain passageways for flow of aqueous humor. In this study, we observed that human trabecular meshwork explants treated with dexamethasone released exosomes with significantly reduced amounts of fibronectin bound per exosome. Further, we found that exosome-fibronectin binding is heparan sulfate-dependent, consistent with our observation that trabecular meshwork exosomes are enriched in the heparin/heparan sulfate binding annexins A2 and A6. In this way, dexamethasone-treated explants released exosomes with a significant reduction in annexin A2 and A6 per exosome. Interestingly, we did not detect exosomal matrix metalloproteinases, but we identified abundant dipeptidyl peptidase 4, a serine protease whose activity was reduced on exosomes isolated from dexamethasone-treated explants. Together, our findings demonstrate mechanistically how corticosteroid-induced alterations in exosomal adhesion cargo and properties can account for the pathological matrix accumulation seen in many glaucoma patients.

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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2016

Volume

11

Issue

10

Start / End Page

e0165326

Location

United States

Related Subject Headings

  • Trabecular Meshwork
  • Protein Binding
  • Nanoparticles
  • Humans
  • Heparitin Sulfate
  • General Science & Technology
  • Fibronectins
  • Extracellular Matrix
  • Exosomes
  • Dexamethasone
 

Citation

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Dismuke, W. M., Klingeborn, M., & Stamer, W. D. (2016). Mechanism of Fibronectin Binding to Human Trabecular Meshwork Exosomes and Its Modulation by Dexamethasone. PLoS One, 11(10), e0165326. https://doi.org/10.1371/journal.pone.0165326
Dismuke, W Michael, Mikael Klingeborn, and W Daniel Stamer. “Mechanism of Fibronectin Binding to Human Trabecular Meshwork Exosomes and Its Modulation by Dexamethasone.PLoS One 11, no. 10 (2016): e0165326. https://doi.org/10.1371/journal.pone.0165326.
Dismuke, W. Michael, et al. “Mechanism of Fibronectin Binding to Human Trabecular Meshwork Exosomes and Its Modulation by Dexamethasone.PLoS One, vol. 11, no. 10, 2016, p. e0165326. Pubmed, doi:10.1371/journal.pone.0165326.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2016

Volume

11

Issue

10

Start / End Page

e0165326

Location

United States

Related Subject Headings

  • Trabecular Meshwork
  • Protein Binding
  • Nanoparticles
  • Humans
  • Heparitin Sulfate
  • General Science & Technology
  • Fibronectins
  • Extracellular Matrix
  • Exosomes
  • Dexamethasone