| First Author | Borkham-Kamphorst E | Year | 2015 |
| Journal | Biochem Biophys Res Commun | Volume | 457 |
| Issue | 3 | Pages | 307-13 |
| PubMed ID | 25576870 | Mgi Jnum | J:220351 |
| Mgi Id | MGI:5634248 | Doi | 10.1016/j.bbrc.2014.12.106 |
| Citation | Borkham-Kamphorst E, et al. (2015) Platelet-derived growth factor-D modulates extracellular matrix homeostasis and remodeling through TIMP-1 induction and attenuation of MMP-2 and MMP-9 gelatinase activities. Biochem Biophys Res Commun 457(3):307-13 |
| abstractText | Platelet-derived growth factor-D (PDGF-D) is a more recent recognized growth factor involved in the regulation of several cellular processes, including cell proliferation, transformation, invasion, and angiogenesis by binding to and activating its cognate receptor PDGFR-beta. After bile duct ligation or in the carbon tetrachloride-induced hepatic fibrosis model, PDGF-D showed upregulation comparable to PDGF-B. Moreover, adenoviral PDGF-D gene transfer induced hepatic stellate cell proliferation and liver fibrosis. We here investigated the molecular mechanism of PDGF-D involvement in liver fibrogenesis. Therefore, the GRX mouse cell line was stimulated with PDGF-D and evaluated for fibrotic markers and PDGF-D signaling pathways in comparison to the other PDGF isoforms. We found that PDGF-D failed to enhance Col I and alpha-smooth muscle actin (alpha-SMA) production but has capacity to upregulate expression of the tissue inhibitor of metalloprotease 1 (TIMP-1) resulting in attenuation of MMP-2 and MMP-9 gelatinase activity as indicated by gelatinase zymography. This phenomenon was restored through application of a PDGF-D neutralizing antibody. Unexpectedly, PDGF-D incubation decreased both PDGFR-alpha and -beta in mRNA and protein levels, and PDGF-D phosphorylated typrosines specific for PDGFR-alpha and -beta. We conclude that PDGF-D intensifies fibrogenesis by interfering with the fibrolytic activity of the TIMP-1/MMP system and that PDGF-D signaling is mediated through both PDGF-alpha and -beta receptors. |
