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

Dismuke, W Michael ; Klingeborn, Mikael ; Stamer, W Daniel Acott, Ted S

PloS one, 2016-10, Vol.11 (10), p.e0165326 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Mechanism of Fibronectin Binding to Human Trabecular Meshwork Exosomes and Its Modulation by Dexamethasone
Autor: Dismuke, W Michael ; Klingeborn, Mikael ; Stamer, W Daniel
Acott, Ted S
Assuntos: Accumulation ; Adhesion ; Annexin A2 - chemistry ; Annexin A2 - metabolism ; Annexin A6 - chemistry ; Annexin A6 - metabolism ; Annexins ; Anti-Inflammatory Agents - pharmacology ; Binding ; Biology and Life Sciences ; Cell adhesion & migration ; Cells, Cultured ; Cellular structure ; Central nervous system depressants ; Corticosteroids ; Culture Media, Serum-Free - chemistry ; Dexamethasone ; Dexamethasone - pharmacology ; Dipeptidyl-peptidase IV ; Exosomes ; Exosomes - chemistry ; Exosomes - drug effects ; Exosomes - metabolism ; Explants ; Extracellular matrix ; Extracellular Matrix - metabolism ; Fibronectin ; Fibronectins ; Fibronectins - chemistry ; Fibronectins - metabolism ; Glaucoma ; Glucocorticoids ; Growth factors ; Heparan sulfate ; Heparin ; Heparitin Sulfate - chemistry ; Heparitin Sulfate - metabolism ; Homeostasis ; Hostages ; Humans ; Hypertension ; Matrix metalloproteinases ; Medicine and Health Sciences ; Nanoparticles - chemistry ; Nanoparticles - metabolism ; Ophthalmology ; Passageways ; Peptidase ; Physical Sciences ; Protein Binding ; Proteins ; Serine ; Serine proteinase ; Steroids ; Steroids (Organic compounds) ; Sulfates ; Trabecular Meshwork - cytology ; Trabecular Meshwork - drug effects ; Trabecular Meshwork - metabolism
É parte de: PloS one, 2016-10, Vol.11 (10), p.e0165326
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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Competing Interests: The authors have declared that no competing interests exist.
Conceptualization: WMD MK WDS. Data curation: WMD. Formal analysis: WMD. Funding acquisition: WMD WDS. Investigation: WMD. Methodology: WMD MK WDS. Resources: WMD MK WDS. Supervision: WMD WDS. Validation: WMD. Visualization: WMD WDS. Writing – original draft: WMD MK WDS. Writing – review & editing: WMD WDS.
Descrição: 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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

Dismuke, W Michael ; Klingeborn, Mikael ; Stamer, W Daniel Acott, Ted S

United States: Public Library of Science

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