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

TLDR

Connective tissue growth factor (CTGF) is a 36‑ to 38‑kDa peptide selectively induced by transforming growth factor‑beta (TGF‑β) in fibroblastic cells. The study compared the biologic activities of CTGF with TGF‑β on fibroblasts in culture and in animal models of fibroplasia. The authors evaluated CTGF and TGF‑β effects on fibroblasts in vitro and in vivo, using monolayer cultures and neonatal mouse injection models. CTGF stimulated fibroblast proliferation and extracellular matrix production in vitro, upregulated collagen, integrin, and fibronectin transcripts and proteins, and when injected into neonatal mice induced granulation tissue and fibrosis, while also being upregulated by TGF‑β in dermal fibroblasts, demonstrating that CTGF promotes connective tissue growth similarly to TGF‑β.

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.