Regulation of fibrogenic/fibrolytic genes by platelet-derived growth factor C, a novel growth factor, in human dermal fibroblasts

Platelet‐derived growth factor (PDGF) is a potent mitogenic and chemotactic cytokine, and PDGF‐C is a novel growth factor belonging to the PDGF family. In this study, to determine whether this growth factor can contribute to fibrosis and tissue remodeling, we examined the effect of PDGF‐CC on the expression of fibrogenic/fibrolytic genes such as type I collagen, fibronectin (FN), matrix metalloproteinases (MMPs), and their inhibitors (TIMPs) in normal human dermal fibroblasts in vitro. PDGF elevated the levels of MMP‐1 or TIMP‐1 protein as well as mRNA, whereas this cytokine had no influence on the expression of type I collagen, FN, or TIMP‐2. PDGF‐CC also increased the levels of MMP‐1 catalytic activity in the cultured media and mRNA expression, which was paralleled that on the levels of promoter activation. Additionally, PDGF‐CC induced the mitogenic and migratory activity of human dermal fibroblasts in a dose‐dependent manner. On the other hand, we also determined the specificity of the inhibitory effect of monoclonal antibodies against PDGF‐CC generated by immunizing balb/c mice with recombinant human PDGF‐CC. This antibody could inhibit the regulatory effects of MMP‐1 or TIMP‐1 synthesis as well as the mitogenic effects on human dermal fibroblasts induced by PDGF‐CC, whereas this antibody did not affect those induced by other PDGF forms such as PDGF‐AA, ‐AB, or ‐BB. These results suggest that this cytokine plays a role in the tissue remodeling. © 2004 Wiley‐Liss, Inc.