Platelet-derived Growth factor-D Modulates Extracellular Matrix Homeostasis and Remodeling Through TIMP-1 Induction and Attenuation of MMP-2 and MMP-9 Gelatinase Activities

Biochem Biophys Res Commun. 2015 Feb 13;457(3):307-13. doi: 10.1016/j.bbrc.2014.12.106. Epub 2015 Jan 7.

Abstract

Platelet-derived growth factor-D (PDGF-D) is a more recent recognized growth factor involved in the regulation of several cellular processes, including cell proliferation, transformation, invasion, and angiogenesis by binding to and activating its cognate receptor PDGFR-β. After bile duct ligation or in the carbon tetrachloride-induced hepatic fibrosis model, PDGF-D showed upregulation comparable to PDGF-B. Moreover, adenoviral PDGF-D gene transfer induced hepatic stellate cell proliferation and liver fibrosis. We here investigated the molecular mechanism of PDGF-D involvement in liver fibrogenesis. Therefore, the GRX mouse cell line was stimulated with PDGF-D and evaluated for fibrotic markers and PDGF-D signaling pathways in comparison to the other PDGF isoforms. We found that PDGF-D failed to enhance Col I and α-smooth muscle actin (α-SMA) production but has capacity to upregulate expression of the tissue inhibitor of metalloprotease 1 (TIMP-1) resulting in attenuation of MMP-2 and MMP-9 gelatinase activity as indicated by gelatinase zymography. This phenomenon was restored through application of a PDGF-D neutralizing antibody. Unexpectedly, PDGF-D incubation decreased both PDGFR-α and -β in mRNA and protein levels, and PDGF-D phosphorylated typrosines specific for PDGFR-α and -β. We conclude that PDGF-D intensifies fibrogenesis by interfering with the fibrolytic activity of the TIMP-1/MMP system and that PDGF-D signaling is mediated through both PDGF-α and -β receptors.

Keywords: Extracellular matrix; MMP; PDGF; Receptors; Signaling; TIMP-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing
  • Becaplermin
  • Cell Line
  • Collagen Type I / genetics
  • Down-Regulation
  • Extracellular Matrix / metabolism
  • Fibrinolysis
  • Homeostasis
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism
  • Lymphokines / antagonists & inhibitors
  • Lymphokines / immunology
  • Lymphokines / metabolism*
  • MAP Kinase Signaling System
  • Matrix Metalloproteinase 2 / metabolism*
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice
  • Platelet-Derived Growth Factor / antagonists & inhibitors
  • Platelet-Derived Growth Factor / immunology
  • Platelet-Derived Growth Factor / metabolism*
  • Proto-Oncogene Proteins c-sis / metabolism
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Signal Transduction
  • Tissue Inhibitor of Metalloproteinase-1 / biosynthesis*

Substances

  • Antibodies, Neutralizing
  • Collagen Type I
  • Lymphokines
  • Pdgfd protein, mouse
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • Timp1 protein, mouse
  • Tissue Inhibitor of Metalloproteinase-1
  • Becaplermin
  • Receptor, Platelet-Derived Growth Factor alpha
  • Receptor, Platelet-Derived Growth Factor beta
  • Matrix Metalloproteinase 2
  • Mmp2 protein, mouse
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse