Display Settings:

Format

Send to:

Choose Destination
Biochim Biophys Acta. 2014 Feb;1842(2):318-25. doi: 10.1016/j.bbadis.2013.11.013. Epub 2013 Nov 19.

Tissue-type plasminogen activator is not necessary for platelet-derived growth factor-c activation.

Author information

  • 1Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Surgery, University of Washington School of Medicine, Seattle, WA 98195, USA.
  • 2Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA.
  • 3Bristol Meyers Squibb, 1201 Eastlake Avenue East, Seattle, WA 98102, USA.
  • 4Department of Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA. Electronic address: campjs@u.washington.edu.

Abstract

Platelet-derived growth factors (PDGFs) are critical for development; their over-expression is associated with fibrogenesis. Full-length PDGF-C is secreted as an inactive dimer, requiring cleavage to allow receptor binding. Previous studies indicate that tissue-type plasminogen activator (tPA) is the specific protease that performs this cleavage; in vivo confirmation is lacking. We demonstrate that primary hepatocytes from tpa KO mice produce less cleaved active PDGF-CC than do wild type hepatocytes, suggesting that tPA is critical for in vitro activation of this growth factor. We developed mice that over-express full-length human PDGF-C in the liver; these mice develop progressive liver fibrosis. To test whether tPA is important for cleavage and activation of PDGF-C in vivo, we intercrossed PDGF-C transgenic (Tg) and tpa knock-out (KO) mice, anticipating that lack of tPA would result in decreased fibrosis due to lack of hPDGF-C cleavage. To measure levels of cleaved, dimerized PDGF-CC in sera, we developed an ELISA that specifically detects cleaved PDGF-CC. We report that the absence of tpa does not affect the phenotype of `PDGF-C Tg mice. PDGF-C Tg mice lacking tPA have high serum levels of cleaved growth factor, significant liver fibrosis, and gene expression alterations similar to those of PDGF-C Tg mice with intact tPA. Furthermore, urokinase plasminogen activator and plasminogen activator inhibitor-1 expression are increased in PDGF-C Tg; tpa KO mice. Our ELISA data suggest a difference between in vitro and in vivo activation of this growth factor, and our mouse model confirms that multiple proteases cleave and activate PDGF-C in vivo.

Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

KEYWORDS:

BrdU; CUB; ECM; H&E; HCC; IP; KO; Liver fibrosis; NPC; PAI-1; PDGF; Plasminogen activator; Platelet-derived growth factor; Tg; bromodeoxyuridine; complement subcomponents Clr/Cls, Uegf, Bmp1; extracellular matrix; hematoxylin & eosin; hepatocellular carcinoma; intraperitoneally; knock-out; non-parenchymal cell; plasminogen activator inhibitor-1; platelet-derived growth factor; tPA; tissue-type plasminogen activator; transgenic; uPA; urokinase plasminogen activator

PMID:
24269585
[PubMed - indexed for MEDLINE]
PMCID:
PMC3932705
[Available on 2015/2/1]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Write to the Help Desk