Mediation of Transforming Growth factor-beta(1)-stimulated Matrix Contraction by Fibroblasts: A Role for Connective Tissue Growth Factor in Contractile Scarring

Am J Pathol. 2003 Nov;163(5):2043-52. doi: 10.1016/s0002-9440(10)63562-6.

Abstract

Excessive cell-mediated tissue contraction after injury can lead to morbid contractile scarring in the body. In the eye this can cause blindness because of posterior capsule opacification, proliferative vitroretinopathy, failure of glaucoma filtration surgery, and corneal haze. During repair, transforming growth factor (TGF)-beta and connective tissue growth factor (CTGF) genes are co-ordinately expressed. Although TGF-beta and CTGF stimulate new matrix deposition, their role and regulation during contractile scarring is unknown. In this study, an in vitro model of collagen matrix contraction culminating from tractional forces generated by fibroblasts showed that both TGF-beta(1) and CTGF-stimulated contraction. Using a specific anti-sense oligodeoxynucleotide to CTGF the procontractile activity of TGF-beta(1) was found to be mediated by CTGF. During contraction fibroblasts produced similar levels of matrix metalloproteinases (MMPs)-2 and -9 with TGF-beta(1) or CTGF and a modest increase in MMP-1 with CTGF only (indicated by zymography and enzyme-linked immunosorbent assay). The requirement of MMPs for contraction was demonstrated using a broad-spectrum synthetic inhibitor. This study demonstrates a new function for CTGF in mediating matrix contraction by fibroblasts involving MMPs and suggests a novel regulatory mechanism for TGF-beta-stimulated contraction. Inhibition of CTGF activity or gene transcription could be a suitable target for anti-scarring therapies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Northern
  • Cells, Cultured
  • Cicatrix / metabolism*
  • Collagen / drug effects
  • Connective Tissue Growth Factor
  • Enzyme Inhibitors / pharmacology
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Matrix / drug effects*
  • Fibroblasts / drug effects
  • Fibroblasts / physiology*
  • Humans
  • Immediate-Early Proteins / drug effects
  • Immediate-Early Proteins / metabolism*
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Matrix Metalloproteinase 2 / drug effects
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / drug effects
  • Matrix Metalloproteinase 9 / metabolism
  • Oligonucleotides, Antisense / pharmacology
  • RNA, Messenger / analysis
  • Sulfur Oxides
  • Transcription, Genetic
  • Transforming Growth Factor beta / pharmacology*
  • Transforming Growth Factor beta1

Substances

  • CCN2 protein, human
  • Enzyme Inhibitors
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • Oligonucleotides, Antisense
  • RNA, Messenger
  • Sulfur Oxides
  • TGFB1 protein, human
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Connective Tissue Growth Factor
  • thionyl bromide
  • Collagen
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9