Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP

FASEB J. 1999 Oct;13(13):1774-86.


Connective tissue growth factor (CTGF) is a cysteine-rich peptide synthesized and secreted by fibroblastic cells after activation with transforming growth factor beta (TGF-beta) that acts as a downstream mediator of TGF-beta-induced fibroblast proliferation. We performed in vitro and in vivo studies to determine whether CTGF is also essential for TGF-beta-induced fibroblast collagen synthesis. In vitro studies with normal rat kidney (NRK) fibroblasts demonstrated CTGF potently induces collagen synthesis and transfection with an antisense CTGF gene blocked TGF-beta stimulated collagen synthesis. Moreover, TGF-beta-induced collagen synthesis in both NRK and human foreskin fibroblasts was effectively blocked with specific anti-CTGF antibodies and by suppressing TGF-beta-induced CTGF gene expression by elevating intracellular cAMP levels with either membrane-permeable 8-Br-cAMP or an adenylyl cyclase activator, cholera toxin (CTX). cAMP also inhibited collagen synthesis induced by CTGF itself, in contrast to its previously reported lack of effect on CTGF-induced DNA synthesis. In animal assays, CTX injected intradermally in transgenic mice suppressed TGF-beta activation of a human CTGF promoter/lacZ reporter transgene. Both 8-Br-cAMP and CTX blocked TGF-beta-induced collagen deposition in a wound chamber model of fibrosis in rats. CTX also reduced dermal granulation tissue fibroblast population increases induced by TGF-beta in neonatal mice, but not increases induced by CTGF or TGF-beta combined with CTGF. Our data indicate that CTGF mediates TGF-beta-induced fibroblast collagen synthesis and that in vivo blockade of CTGF synthesis or action reduces TGF-beta-induced granulation tissue formation by inhibiting both collagen synthesis and fibroblast accumulation.

Publication types

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

MeSH terms

  • 8-Bromo Cyclic Adenosine Monophosphate / pharmacology
  • Animals
  • Cholera Toxin / pharmacology
  • Collagen / biosynthesis*
  • Connective Tissue Growth Factor
  • Cyclic AMP / pharmacology*
  • DNA, Antisense
  • Down-Regulation
  • Drug Interactions
  • Fibroblasts
  • Fibrosis / etiology
  • Gene Expression / drug effects
  • Genes, Reporter
  • Granulation Tissue / drug effects
  • Growth Substances / genetics
  • Growth Substances / immunology
  • Growth Substances / pharmacology*
  • Humans
  • Immediate-Early Proteins*
  • Intercellular Signaling Peptides and Proteins*
  • Mice
  • Mice, Transgenic
  • Rats
  • Transforming Growth Factor beta / pharmacology*


  • CCN2 protein, human
  • CCN2 protein, mouse
  • CCN2 protein, rat
  • DNA, Antisense
  • Growth Substances
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • Transforming Growth Factor beta
  • Connective Tissue Growth Factor
  • 8-Bromo Cyclic Adenosine Monophosphate
  • Collagen
  • Cholera Toxin
  • Cyclic AMP