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

Abstract

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.

Expression of platelet‐derived growth factors C and D in the synovial membrane of patients with rheumatoid arthritis and osteoarthritis

“…Indeed, in the present study, stimulation with PDGF-D increased the expression of MMP-1 mRNA in RA synovial fibroblasts. Similar results for PDGF-D have been reported in the case of MMP-2 in vascular smooth muscle cells (31), for MMP-9 in renal carcinoma cells (33), as well as for PDGF-C with respect to MMP-1 expression in dermal fibroblasts (32). Taken together, these findings indicate the relevance of the protease-activated PDGF isoforms in tissue remodeling, a process of major importance during the progression of arthritic diseases.…”

Potential Therapeutic Targets for Cardiac Fibrosis

“…59,60 In addition, PGDF stimulates fibroblasts to contract collagen matrices and differentiate into myofibroblasts in vitro. 61,62 PDGF␤ receptors are expressed by activated microvascular pericytes in patients with early systemic sclerosis, but not in those with late-stage scleroderma. 63 Pericytes fail to develop in PDGF␤ receptor deficient embryos.…”

Imatinib Mesylate Attenuates Myocardial Remodeling Through Inhibition of Platelet-Derived Growth Factor and Transforming Growth Factor Activation in a Rat Model of Hypertension

“…6 PDGF stimulates fibroblasts to contract collagen matrices and differentiate into myofibroblasts. 7,8 PDGF comprises a family of homo-or heterodimeric growth factors, including PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD. These isoforms act via 2 receptor tyrosine kinases: PDGF receptors-α (PDGFR-α) and β (PDGFR-β).…”