Stimulation of Fibroblast Cell Growth, Matrix Production, and Granulation Tissue Formation by Connective Tissue Growth Factor

Abstract

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.

MicroRNA‐503 promotes angiotensin II‐induced cardiac fibrosis by targeting Apelin‐13

“…The TGF‐β‐CTGF pathway activated cells with a fibrogenetic phenotype and initiated cellular processes underlying fibrosis 30, 31. Connective tissue growth factor has also been involved in the induction of cardiac fibrosis in animal models of LV remodelling 32, 33. In our study, we observed that overexpression of miR‐503 increased the expression of TGF‐β and CTGF in CFs, an effect that was abolished by the co‐application of Apelin‐13.…”

A novel primate model of delayed wound healing in diabetes: dysregulation of connective tissue growth factor

“…Early studies described the functions of CTGF as connective tissue cell proliferation, differentiation, chemotaxis and adhesion [8,9,43]. CTGF is synthesised by fibroblasts and stimulates the proliferation and chemotaxis of these cells as well as the production of various ECM components in fibroblast cultures, including collagen I, fibronectin and collagen IV [44,45]. CTGF is produced at increased levels during normal wound repair [8] and at sites of fibrogenesis [11,45].…”

Expression and differential regulation of connective tissue growth factor in pancreatic cancer cells

“…Only treatment with TGFb was accompanied by a parallel induction of collagen I transcription, whereas the early transient increase of CTGF induced by EGF/TGFa did not alter collagen I transcription. It has been speculated that CTGF is a downstream mediator of TGFb actions on the ECM, on the proliferation of ®broblasts and the development of ®brosis (Grotendorst, 1997;Frazier et al, 1996;Grotendorst et al, 1996). This is of paramount importance for the pathogenesis of pancreatic diseases as e.g.…”

“…In this context Grotendorst and colleagues recently identi®ed a new TGFb responsive element located in the CTGF-promoter . Recombinant CTGF has recently been shown to stimulate type I collagen and ®bronectin production in NRK ®broblasts (Frazier et al, 1996). CTGF could thus be a downstream e ector of TGFb which is a potent stimulator of extracellular matrix production.…”