PDGFRα plays a crucial role in connective tissue remodeling

Abstract

Platelet derived growth factor (PDGF) plays a pivotal role in the remodeling of connective tissues. Emerging data indicate the distinctive role of PDGF receptor-α (PDGFRα) in this process. In the present study, the Pdgfra gene was systemically inactivated in adult mouse (α-KO mouse), and the role of PDGFRα was examined in the subcutaneously implanted sponge matrices. PDGFRα expressed in the fibroblasts of Pdgfra-preserving control mice (Flox mice), was significantly reduced in the sponges in α-KO mice. Neovascularized areas were largely suppressed in the α-KO mice than in the Flox mice, whereas the other parameters related to the blood vessels and endothelial cells were similar. The deposition of collagen and fibronectin and the expression of collagen 1a1 and 3a1 genes were significantly reduced in α-KO mice. There was a significantly decrease in the number and dividing fibroblasts in the α-KO mice, and those of macrophages were similar between the two genotypes. Hepatocyte growth factor (Hgf) gene expression was suppressed in Pdgfra-inactivated fibroblasts and connective tissue. The findings implicate the role of PDGFRα-dependent ECM and HGF production in fibroblasts that promotes the remodeling of connective tissue and suggest that PDGFRα may be a relevant target to regulate connective tissue remodeling.

Blockade of PDGF Receptors by Crenolanib Has Therapeutic Effect in Patient Fibroblasts and in Preclinical Models of Systemic Sclerosis

“…While TGF-β is the principal inducer of the ECM proteins, PDGF has also been shown to contribute to matrix production (Horikawa et al, 2015). Therefore, we examined the effect of crenolanib on type I collagen and other selected ECM proteins in healthy dermal (HC) and SSc fibroblasts at the basal level and after TGF-β stimulation.…”

“…The pro-fibrotic function of PDGF is mainly associated with its role as an inducer of proliferation and migration of mesenchymal cells, however PDGF could also contribute to the deposition of ECM proteins (Gabrielli et al, 2007, Horikawa et al, 2015). Herein, we found that PDGFR signaling was required for the basal and TGF-β-induced expression of periostin and CCN2.…”

Pathogenetic significance and possibility as a therapeutic target of platelet derived growth factor

“…Enhancement of the intrinsic PDGFR signal, evoked by mutational activation of Pdgfra, but not Pdgfrb , systemically induced fibroblastic hyperplasia and increased ECM deposition similar to that observed in collagen diseases . Along this line, adult PDGFRα mediates the synthesis of collagen type I α1 and collagen type III α1, and HGF in skin fibroblasts, and induces connective tissue remodeling in the implanted sponge into subcutaneous tissue, in mutant mice with global Pdgfra KO that was induced postnatally . Null KO mice of Pdgfra severely impaired the systemic connective tissue development, whereas the phenotypes of null KO mice of Pdgfrb were mainly detected in association with blood vessels .…”

Effect of Collagen Type I or Human Fibronectin on Imatinib Cytotoxicity in Oral Squamous Cell Carcinoma

“…Imatinib also inhibits other TK receptors such as PDGF and KIT [5]- [7]. PDGFα-dependent ECM and HGF production in fibroblasts promotes remodeling of connective tissue [31]. Additionally, imatinib reduces production of ECM and prevents development of experimental dermal fibrosis [32].…”