Growth Differentiation Factor-9 Promotes Fibroblast Proliferation and Migration in Keloids through the Smad2/3 Pathway

• Published in: Cellular physiology and biochemistry Vol. 40; no. 1-2; pp. 207 - 218
• Main Authors: Jiang, Zhaohua, Yu, Qingxiong, Xia, Lingling, Zhang, Yi, Wang, Xiuxia, Wu, Xiaoli, Gao, Zhen
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland Cell Physiol Biochem Press GmbH & Co KG 2016
• Subjects: Adult; Cell Movement; Cell Proliferation; Cyclooxygenase 2 - metabolism; Female; Fibroblast; Fibroblasts - metabolism; Fibroblasts - pathology; Gene Silencing; Growth Differentiation Factor 9 - genetics; Growth Differentiation Factor 9 - metabolism; Growth differentiation factor-9; Humans; Keloid - enzymology; Keloid - genetics; Keloid - pathology; Keloids; Male; Middle Aged; Original Paper; Signal Transduction; Smad pathway; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Up-Regulation - genetics; Vascular Endothelial Growth Factor C - genetics; Vascular Endothelial Growth Factor C - metabolism; Young Adult; Keloids; Fibroblast; Smad pathway; Growth differentiation factor-9
• ISSN: 1015-8987; 1421-9778
• DOI: 10.1159/000452538

Background: Keloids are fibroproliferative scars that develop as a result of a dysregulated wound healing process; however, the molecular mechanisms of keloid pathogenesis remain unclear. Keloids are characterized by the ability to spread beyond the original boundary of the wound, and they represent a significant clinical challenge. Previous work from our group suggested that growth differentiation factor (GDF)-9 plays a role in the invasive behavior of keloids. Here, we examined the involvement of GDF-9 in keloid formation and spread and elucidated a potential underlying mechanism. Methods: The expression of GDF-9, cyclooxygenase (COX)-2, vascular epidermal growth factor (VEGF)-C, matrix metalloprotease (MMP)-2, MMP-9, transforming growth factor (TGF)-β1, and the related signaling pathway components in human keloid tissues or keloid fibroblasts (kFBs) was monitored by qRT-PCR and western blot. A series of overexpression and silencing experiments in normal and keloid fibroblasts were used to modify the expression of GDF-9. The effects of GDF-9 on kFB proliferation and migration were assessed using the CCK-8, cell cycle and scratch wound healing assays. Results: GDF-9 promotes fibroblast proliferation and migration. GDF-9 silencing in kFBs decreased cell proliferation, blocked cell cycle progression, downregulated the angiogenic markers COX-2 and VEGF-C, and downregulated MMP-2 and MMP-9 expression, whereas it had no effect on the levels of TGF-β1. GDF-9 silencing significantly inhibited Smad2 and Smad3 phosphorylation in kFBs. Conclusions: GDF-9 promotes the proliferation and migration of kFBs via a mechanism involving the Smad2/3 pathway.