Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor.
Connective tissue growth factor (CTGF) is a 36-to 38-kDa peptide that is selectively induced by transforming growth factor-beta (TGF-beta) in fibroblastic cell types. We compared the biologic activities of CTGF with TGF-beta on fibroblasts in culture and in animal models of fibroplasia. CTGF was active as a mitogen in monolayer cultures of normal rat kidney fibroblasts. CTGF did not stimulate anchorage-independent growth of NRK fibroblasts, however, or inhibit the growth of mink lung epithelial cells, distinguishing CTGF's growth-regulatory activities from those of TGF-beta. In NRK fibroblasts, both TGF-beta and CTGF significantly increased the transcripts encoding alpha 1 type I collagen, alpha 5 integrin, and fibronectin. Stimulation of type I collagen and fibronectin protein synthesis by TGF-beta and CTGF was confirmed by pulse labeling of cells with [35S]methionine. Subcutaneous injection of TGF-beta and CTGF into neonatal NIH Swiss mice resulted in a large stimulation of granulation tissue and fibrosis at the site of injection. In situ hybridization studies revealed that TGF-beta injection induced high levels of CTGF mRNA in the dermal fibroblasts at the injection site, demonstrating that TGF-beta can induce the expression of CTGF in connective tissue cells in vivo. No CTGF transcripts were detected in the epidermal cells in either control or TGF-beta-injected skin or in fibroblasts in control (saline-injected) skin. These results demonstrate that, like TGF-beta, CTGF can induce connective tissue cell proliferation and extracellular matrix synthesis.
Frazier
K
K
Department of Cell Biology and Anatomy, University of Miami School of Medicine, FL 33136, USA.
Williams
S
S
Kothapalli
D
D
Klapper
H
H
Grotendorst
G R
GR
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D055513:Connective Tissue Growth Factor; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D006097:Granulation Tissue / Q000187:drug effects* / Q000254:growth & development; D006131:Growth Inhibitors / Q000494:pharmacology; D006133:Growth Substances / Q000235:genetics / Q000494:pharmacology*; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D008934:Mitogens / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins; D012867:Skin / Q000187:drug effects / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C526318:CCN2 protein, mouse; C526316:CCN2 protein, rat; D016326:Extracellular Matrix Proteins; D006131:Growth Inhibitors; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008934:Mitogens; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D055513:Connective Tissue Growth Factor