10506580

pubmed:Citation

13

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.

eng

IM

MEDLINE

0892-6638

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1774-86

pubmed-meshheading:10506580-8-Bromo Cyclic Adenosine Monophosphate, pubmed-meshheading:10506580-Animals, pubmed-meshheading:10506580-Cholera Toxin, pubmed-meshheading:10506580-Collagen, pubmed-meshheading:10506580-Connective Tissue Growth Factor, pubmed-meshheading:10506580-Cyclic AMP, pubmed-meshheading:10506580-DNA, Antisense, pubmed-meshheading:10506580-Down-Regulation, pubmed-meshheading:10506580-Drug Interactions, pubmed-meshheading:10506580-Fibroblasts, pubmed-meshheading:10506580-Fibrosis, pubmed-meshheading:10506580-Gene Expression, pubmed-meshheading:10506580-Genes, Reporter, pubmed-meshheading:10506580-Granulation Tissue, pubmed-meshheading:10506580-Growth Substances, pubmed-meshheading:10506580-Humans, pubmed-meshheading:10506580-Immediate-Early Proteins, pubmed-meshheading:10506580-Intercellular Signaling Peptides and Proteins, pubmed-meshheading:10506580-Mice, pubmed-meshheading:10506580-Mice, Transgenic, pubmed-meshheading:10506580-Rats, pubmed-meshheading:10506580-Transforming Growth Factor beta

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

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