RRC ID 34819
著者 Makino K, Jinnin M, Aoi J, Hirano A, Kajihara I, Makino T, Sakai K, Fukushima S, Inoue Y, Ihn H.
タイトル Discoidin domain receptor 2-microRNA 196a-mediated negative feedback against excess type I collagen expression is impaired in scleroderma dermal fibroblasts.
ジャーナル J Invest Dermatol
Abstract Systemic sclerosis (SSc) is characterized by excess collagen deposition in the skin, due to intrinsic transforming growth factor-β (TGF-β) activation. We tried to determine the expression and the role of discoidin domain receptor 2 (DDR2) in SSc. The expression of DDR2 mRNA and protein was significantly decreased in SSc dermal fibroblasts, which was recovered by knocking down TGF-β. The knockdown of DDR2 in normal fibroblasts induced microRNA-196a expression, which led to type I collagen downregulation, indicating that DDR2 itself has a negative effect on microRNA-196a expression and inducible effect on collagen expression. In SSc fibroblasts, however, the DDR2 knockdown did not affect TGF-β signaling and microRNA-196a expression. The microRNA-196a levels were significantly decreased in normal fibroblasts treated with TGF-β and in SSc fibroblasts. Taken together our data indicate that, in SSc fibroblasts, intrinsic TGF-β stimulation induces type I collagen expression, and also downregulates DDR2 expression. This probably acts as a negative feedback mechanism against excess collagen expression, as a decreased DDR2 expression is supposed to stimulate the microRNA-196a expression and further change the collagen expression. However, in SSc fibroblasts the microRNA-196a expression was downregulated by TGF-β signaling. DDR2-microRNA-196a pathway may be a previously unreported negative feedback system, and its impairment may be involved in the pathogenesis of SSc.
巻・号 133(1)
ページ 110-9
公開日 2013-1-1
DOI 10.1038/jid.2012.252
PII S0022-202X(15)35961-3
PMID 22832484
MeSH Cells, Cultured Collagen Type I / biosynthesis* Dermis / drug effects Dermis / metabolism* Dermis / pathology Discoidin Domain Receptors Feedback, Physiological / drug effects Feedback, Physiological / physiology* Fibroblasts / drug effects Fibroblasts / metabolism* Fibroblasts / pathology Gene Expression Regulation / drug effects Gene Expression Regulation / physiology Gene Knockdown Techniques Humans MicroRNAs / genetics MicroRNAs / metabolism* Receptor Protein-Tyrosine Kinases / genetics Receptor Protein-Tyrosine Kinases / metabolism* Receptors, Mitogen / genetics Receptors, Mitogen / metabolism* Scleroderma, Systemic / drug therapy Scleroderma, Systemic / metabolism* Signal Transduction / drug effects Signal Transduction / physiology Transforming Growth Factor beta / genetics Transforming Growth Factor beta / metabolism Transforming Growth Factor beta / pharmacology
IF 7.143
引用数 26
WOS 分野 DERMATOLOGY
リソース情報
遺伝子材料 pCAG-HIVgp (RDB04394) pCMV-VSV-G-RSV-Rev (RDB04393) CSII-EF-RfA (RDB04387).