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-β (TGF-β) in fibroblastic cell types. We compared the biologic activities of CTGF with TGF-β 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-β. In NRK fibroblasts, both TGF-β and CTGF significantly increased the transcripts encoding α1 type I collagen, α5 integrin, and fibronectin. Stimulation of type I collagen and fibronectin protein synthesis by TGF-β and CTGF was confirmed by pulse labeling of cells with [35S]methionine. Subcutaneous injection of TGF-β 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-β injection induced high levels of CTGF mRNA in the dermal fibroblasts at the injection site, demonstrating that TGF-β 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-β-injected skin or in fibroblasts in control (saline-injected) skin. These results demonstrate that, like TGF-β, CTGF can induce connective tissue cell proliferation and extracellular matrix synthesis.